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Findling R, Taylor-Zapata P, Anand R, et al.; Eunice Kennedy Shriver National Institute of Child Health and Human Development. A Randomized, Double-Blind, Placebo Controlled Study of the Efficacy of Lithium for the Treatment of Pediatric Mania Followed by an Open Label Long-Term Safety Period, Double-Blind, Placebo-Controlled Discontinuation Phase, and Open Label Restabilization Period (COLT2) [Internet]. Bethesda (MD): National Institute of Child Health and Human Development (US); 2015 Dec 1.
A Randomized, Double-Blind, Placebo Controlled Study of the Efficacy of Lithium for the Treatment of Pediatric Mania Followed by an Open Label Long-Term Safety Period, Double-Blind, Placebo-Controlled Discontinuation Phase, and Open Label Restabilization Period (COLT2) [Internet].
Show detailsAll participants entering a study phase received at least one dose of study medication in that phase and are included in the safety population. This includes 81 participants in the Efficacy Phase; 44 participants in the Long-Term Effectiveness Phase; 31 participants in the Discontinuation Phase; and 13 participants in the Restabilization Phase. For the Safety Section, the participants are grouped by the treatment actually received during the phase (not the randomized treatment).
Adverse Events
An adverse event (AE) is defined as any untoward medical occurrence in a clinical investigation participant. Treatment emergent adverse events (TEAEs) are those AEs that occur after administration of the study product and are therefore temporally associated with the use of the study product. Pre-existing conditions are not considered AEs unless they worsen in intensity or frequency during the course of the clinical investigation.
An AE is counted in the phase the AE originated in. For example, if an AE started in the Efficacy Phase and continued into the Long-Term Effectiveness Phase, it was counted only in the Efficacy Phase. AEs in the LTE Phase are defined as those AEs originating in that phase.
Concomitant Therapy
This study collected information on all prescribed or OTC medications taken from 7 days prior to the date of consent (screening visit) through to study termination. This includes all adjunctive medication, psychotropic medications and psychotherapy. Medications/therapies were reported during the phase in which they were used. For example, if a participant was on Claritin for the entire time period of the study, Claritin use will be reported in each phase for that participant.
Clinical Laboratory Evaluations
Descriptive summaries (mean, standard deviation (SD), 95% confidence interval (CI) of mean, median, minimum, and maximum) of observed values and changes from baseline to end-of-phase values are presented by treatment group for hematology clinical laboratory values in Table 14.3.3.1; chemistry clinical laboratory values in Table 14.3.3.2; clinical thyroid panel in Table 14.3.3.3; laboratory urinalysis measurements in Table 14.3.3.4; and laboratory coagulation measurements in Table 14.3.3.5.
Vital Signs
At each office visit, heart rate, systolic blood pressure, diastolic blood pressure, and weight were measured. Height was collected at screening, Efficacy Phase Day 1, and the end of each study phase. The standardized weight, height, and BMI Z scores are calculated by adjusting for the appropriate population, age- and sex-specific levels for the normal population provided by 2000 CDC growth charts. Standardized blood pressure Z scores were calculated by adjusting for the appropriate population, age-, sex- and standardized height specific levels from the normal population in a method provided by Fourth Report on the Diagnosis, Evaluation and Treatment of High Blood Pressure in Children and Adolescents from May 2005. Blood pressure Z scores were calculated using the height Z score. Baseline height Z score for each phase was used for all visits except last visit in the phase (i.e. the LOCF visit).
Electrocardiogram
Electrocardiogram (ECG) was completed on all participants at screening and the end of each study phase.
12.1. Screening Phase
12.1.1. Adverse Events and Tolerability
12.1.1.1. Summary of Treatment Emergent Adverse Events
Adverse events were collected during the Screening Phase. The Screening Phase could last from 3 to 30 days. Thirty-two participants reported 41 AEs during the Screening Phase. Most common AE reported was headache in 6 participants. Two participants reported SAEs: one with increased agitation [▬] who terminated due to this AE and one [▬] with aggression who withdrew consent because they didn’t want to wash out of the medication started for this AE. AEs occurring during the Screening Phase are summarized in Appendix 16.2.
12.1.2. Concomitant Therapy
12.1.2.1. Concomitant Medications
Appendix 16.2 summarizes all concomitant medications reported during the Screening Phase. This includes all concomitant medications taken from 7 days prior to the screening visit through randomization to the Efficacy Phase or study termination, if ineligible to continue. Most commonly used medications included ibuprofen and paracetamol (acetaminophen) each in 6 participants; cetirizine hydrochloride reported in 5 participants; and montelukast sodium and loratadine in 4 participants each.
Only 4 participants (with 5 medications) who failed the Screening Phase listed concomitant medications. These medications included mineral supplements, ascorbic acid combinations, multivitamins, salbutamol, and oxybutynin.
12.1.2.2. Concomitant Psychotropic Medications
Twelve participants received lorazepam during the screening phase; 11 participants received risperidone; 7 participants received melatonin; and 6 participants each received aripiprazole, hydroxyzine, and valproate sodium. See the summary in Appendix 16.2.
There were 42 participants that received psychotropic medications at the Screening Phase that went on to be randomized into the Efficacy Phase. The medications most frequently used by these participants included lorazepam (N=11); risperidone (N=11); hydroxyzine (N=6); melatonin (N=6); and valproate sodium (N=6).
12.1.2.3. Concomitant Psychotherapy
There were 36 concomitant psychotherapies reported during screening, in 28 participants that were randomized to the Efficacy Phase. This included 19 behavior therapies in 16 participants; 3 cognitive therapies; 9 other therapies; and 5 with unknown therapy type. One non-randomized participant reported other therapy.
12.1.3. Vital Signs, ECG and Physical Examinations
ECGs were completed on 95 participants during the Screening Phase, 23 (24.2%) were reported by the investigator as “abnormal but not clinically significant”. The remaining 72 were reported as normal, shown in Appendix 16.2.
Of the 81 participant randomized to the Efficacy Phase, 21 (25.9%) were recorded as “abnormal but not clinically significant” by the investigator.
12.1.4. Other Safety Evaluations
12.1.4.1. Neurologic Rating Scale
The Neurological Rating Scale at Screening Phase was completed on 93 of the 153 screened participants. Eighty-seven of the 93 completed forms scored 0 on the scale. Two participants each scored 1 and 2. One participant scored 3 (scored 1 on gait, arm dropping and tremor) and one participant scored 4 (1 on glabella tap and 3 on tremor). Both of these participants enrolled in the Efficacy Phase. Listing of Neurologic Rating Scale items is provided in Appendix 16.2.
12.1.4.2. Columbia Suicide Severity Rating Scale
Results of the Lifetime Suicide Rating Scale completed at screening phase are shown in Table 12-1. Eleven percent of participants randomized to the Efficacy Phase reported a history of an active suicide ideation with plan.
Table 12-1
Lifetime Suicide Rating Scale.
12.2. Efficacy Phase
12.2.1. Extent of Exposure
Of the 81 participants who entered the Efficacy phase, 58 (72%) completed all 8 weeks of the phase. During the first 2 weeks of treatment, 6 lithium participants and 3 placebo participants terminated. By the end of 4 weeks, 12 of 16 lithium terminations and 5 of 7 placebo terminations had already occurred. Table 12-2 summarizes the duration on-study.
Table 12-2
Study Week of Termination During the Efficacy Phase.
All participants in the Efficacy Phase received the correct randomized treatment. Summary of study drug dose received by treatment group in the efficacy phase is presented in Table 12-3. Initial dose for participants weighing ≥30 kg was 300 mg TID for a total daily dose of 900 mg. Participants < 30 kg began treatment at 300 mg BID for a total dose 600 mg. Based on the participant’s response and tolerability, the lithium dose could be increased by 300 mg three days after the baseline visit and at weekly visits/phone calls until the maximum tolerated dose was achieved. Maximum study dose was 40 mg/kg. Placebo doses were titrated up as for lithium and were decreased as defined at randomization.
Table 12-3
Summary of Study Drug Total Daily Dose (mg/kg/day) During the Efficacy Phase.
Participants started the study receiving between 7.8 and 30.8 mg/kg/day (median dose 18.5 mg/kg/day). The last reported dose for participants randomized to lithium treatment was between 5.9 and 50.0 mg/kg/day with a median of 30.0 mg/kg/day. Participants randomized to receive placebo were receiving a median of 27.6 mg/kg/day at the end of the phase (range 10.0 – 47.1 mg/kg/day.
Lithium levels were drawn at each in-office visit. Table 12-4 summarizes the last reported lithium level for each group: the participants randomized to lithium had a median value of 1.0 mEq/L with a range of 0.0 −2.0 mEq/L. Doses were not increased once the serum lithium level was >1.4 mEq/L.
Table 12-4
Summary of Last Reported Lithium Level During the Efficacy Phase.
12.2.2. Adverse Events and Tolerability
12.2.2.1. Summary of Treatment Emergent Adverse Events
A summary of TEAEs occurring during the Efficacy Phase is shown in Table 14.3.1.1.1 and Table 12-5 below. Overall, there were 521 adverse events reported in 76 of the 81 safety participants (94%). There was a similar rate of TEAEs in the Lithium (94%) and Placebo (93%) groups; however, the lithium-treated participants report more TEAEs per participant (mean of 7.7) than placebo-treated participants (mean of 4.0 TEAEs per participant). Three lithium participants (with follow-up of 3, 5.7 and 7.7 weeks) and 2 placebo (with follow-up of 1.3 and 8 weeks) participants did not report any TEAEs during the Efficacy Phase.
Table 12-5
Efficacy Phase: Overall Summary of Tolerability by Efficacy Phase Treatment Received Group.
The maximum severity of any TEAE was mild for 19 (36%), moderate for 20 (38%) and severe for 11 (21%) of the 53 lithium treated participants. The 28 placebo-treated participants had a maximum severity of mild in 13 (46%) participants, moderate in 11 (39%) and severe in 2 (7%) participants. Lithium participants had 30/53 (57%) with TEAEs that were probably or definitely related to study drug, compared to 4/28 (14%) of placebo-treated participants. Note that none of the placebo-treated participants had a TEAE definitely related to study medication.
12.2.2.2. Analysis of Adverse Events
12.2.2.2.1. Most Frequently Reported Treatment-Emergent Adverse Events
Table 12-6 summarizes TEAEs reported in ≥ 10% of the participants during the Efficacy Phase. Overall, headache was the most frequently reported TEAE, with 43 events occurring in 28 (35%) of the 81 participants (36% of the lithium-treated participants and 32% of the placebo-treated participants). GI disorders of nausea, vomiting, upper abdominal pain, diarrhea, and dyspepsia were also frequently occurring TEAEs. Nausea was present in 43% of the lithium-treated participants and in 18% of the placebo-treated participants, and vomiting was present in 45% of the lithium-treated participants and in 11% of the placebo-treated participants. Upper abdominal pain was present in 31% of the participants (30% of lithium- and 32% of the placebo-treated participants) and dyspepsia in 13% of lithium and 11% of placebo participants.
Table 12-6
Efficacy Phase: Most Frequently Occurring (≥ 10% of the Participants) Treatment-Emergent Adverse Events by Efficacy Phase Treatment Received Group.
Other frequent TEAEs that occurred more often in the lithium arm (compared to placebo) included tremors (32% vs. 7%); thirst (28% vs. 11%); pollakiuria (26% vs. 7%); dizziness (23% vs. 7%); and increased TSH (17% vs. 0%). Also note that abdominal pain, sedation, and rash each occurred in 6 (11%) of the lithium participants. Placebo participants did not report any sedation or rash, and 1 placebo participant reported abdominal pain.
12.2.2.2.2. Treatment-Emergent Adverse Events by Intensity
There were 15 severe TEAEs in 13 participants: 11 (21%) of the 53 lithium participants and 2 (7%) of the 28 placebo participants. These 15 severe TEAEs included 8 psychiatric disorders (psychotic disorder, suicidal ideation, suicidal behavior, auditory hallucination, aggression, mood altered, agitation, and bipolar disorder); 4 GI disorders (nausea, vomiting, diarrhea, and upper abdominal pain); polydipsia; chest pain; and dysarthria. The placebo group included 2 of the psychiatric disorders (agitation and bipolar disorder).
Of the 521 reported TEAEs, 102 (20%) were moderate. Thirty-one (38%) participants reported a maximum TEAE severity of moderate: 20 (38%) of lithium-treated participants and 11 (39%) of placebo-treated participants.
Of the 521 TEAEs, 404 (78%) were of mild severity, with 36% of lithium participants and 46% of the placebo participants reporting mild as the highest severity.
Table 14.3.1.3.1 summarizes all AEs by SOC, PT and intensity.
12.2.2.3. Treatment-Emergent Adverse Events by Relationship
Five TEAE were considered to be “definitely” related to study medication. These 5 TEAEs were reported in 5 (9%) of the 53 lithium treated participants and included vomiting (n=1), blood thyroid stimulating hormone increased (n=2), dysarthria (n=1) and enuresis (n=1).
There were 110 (21%) of the 521 TEAEs considered to be “probably” related to study medication. 104 occurred in lithium treated participants and 6 occurred in placebo treated participants. The TEAEs probably related in lithium treated participants included 40 gastrointestinal disorders and 28 nervous system disorders. The probably related TEAEs in placebo participants included 5 gastrointestinal disorders and 1 nervous system disorder (somnolence).
249 (48%) of the TEAEs were “possibly” related and 157 (30%) were “unrelated” of the 521 reported TEAEs during the Efficacy Phase. In the lithium arm there were 16 (30%) participants with maximum relatedness of “possibly” and 4 (8%) participants with maximum relatedness of “unrelated”, in the placebo arm there were 18 (64%) participants with “possibly” and 4 (14%) with “unrelated” as maximum relatedness.
Table 14.3.1.4.1 summarizes all AEs by SOC, PT and relationship to study medication.
12.2.2.3.1. Listing of Adverse Events by Participant
A complete listing of all AEs is provided in Appendix 16.2.
12.2.2.3.2. Deaths, Serious Adverse Events and Adverse Events Leading to the Discontinuation of Study Medication
12.2.2.3.2.1. Deaths
There were no participant deaths reported in this study.
12.2.2.3.2.2. Serious Adverse Events
There were 7 SAEs reported in 6 participants during the Efficacy Phase, as summarized in Table 14.3.1.5.1 and Table 12-7. All SAEs were reported as unrelated to study medication.
Table 12-7
Efficacy Phase: Serious Adverse Events by Efficacy Phase Treatment Received Group.
Four (8%) of the 53 lithium participants reported 5 SAEs:
- One lithium participant [▬] reported an SAE of severe aggressive behavior after 3 days in the Efficacy Phase, and 8 days later terminated the study for an SAE of severe altered moods.
- One participant [▬] included suicide threats at 1.4 weeks into the Efficacy Phase, which resulted in study termination.
- One participant [▬] with auditory hallucinations at 3.3 weeks into the Efficacy Phase, which resulted in study termination.
- One participant [▬] reported a broken arm, with no action taken to study medication.
Two (7%) placebo treated participants reported SAEs:
- One participant [▬] with worsening of bipolar symptoms at 5.9 weeks in the Efficacy Phase, which led to study termination.
- One participant [▬] with aggressive behavior at 4.6 weeks in the Efficacy Phase, which lead to study termination..
12.2.2.3.2.3. Adverse Events Leading to the Discontinuation of Study Medication
Six lithium-treated participants had TEAEs that led to study termination in the Efficacy Phase:
- One participant [▬] had nausea, sedation, tremors, and hypotonia (all of mild severity, possibly related to study medication) that led to a temporary stop of study medication. Sixteen days later the participant reported psychosis (of severe severity, probably related to study medication) and terminated from the study.
- Two participants [▬] reported SAE of suicide ideation or behavior with severe severity and unrelated to study medication.
- One participant [▬] with moderate agitation unrelated to study medication
- One participant [▬] with an SAE of severe auditory hallucinations unrelated to study medication.
- One participant [▬] with an SAE of severe altered moods, unrelated to study medication.
Two placebo-treated participants had TEAEs that led to study termination in the Efficacy Phase:
- One participant [▬] reported SAE of worsening bi-polar symptoms of severe severity and unrelated to study medication. This participant was hospitalized and terminated the same day due to suicidal/homicidal ideation.
- One participant [▬ reported an SAE of moderate aggression (hospitalized) unrelated to study medication.
12.2.3. Concomitant Therapy
12.2.3.1. Concomitant Medications
Concomitant medications taken during the Efficacy Phase are reported in Table 14.3.2.1.1. The most commonly used medication was paracetamol (acetaminophen), which was used in 17 (32%) of lithium participants and 7 (25%) of placebo participants. Ibuprofen, a medication prohibited by the protocol, was the second most commonly used concomitant medication. Used in 2 lithium participants and 4 placebo participants, these participants were considered to have major protocol deviations. Amoxicillin, hydrocortizone, and loratadine were each used in 4 participants during the Efficacy Phase.
12.2.3.2. Concomitant Psychotropic Medications
Concomitant psychotropic medications are summarized in Table 14.3.2.2.1 and were used during the Efficacy Phase in 22 (42%) of the lithium participants and 15 (54%) of the placebo participants. The most frequently used psychotropic concomitant medication was lorazepam in 14 (26%) of the lithium participants and 9 (32%) of the placebo participants. Hydroxyzine was used in 11 (21%) of lithium participants and 8 (29%) of placebo participants.
12.2.3.3. Concomitant Psychotherapy
Twenty-four participants received 30 different concomitant psychotherapies during the Efficacy Phase: 17 (32%) of lithium participants and 7 (25%) of placebo participants. The most common type of therapy was behavioral therapy in 14 participants: 10 (19%) lithium (one participant [▬] received both individual and family behavioral therapy) and 4 (14%) placebo participants. Therapy types are summarized in Table 14.3.2.3.1.
12.2.4. Clinical Laboratory Evaluations
Baseline visit of the Efficacy Phase is defined as the laboratory values drawn during screening. Laboratory measurements were completed at baseline (screening) and at Week 2, Week 4, Week 8/End-of-Phase.
Hematology results are shown in Tables 14.3.3.1.1 1-15, Figures 14.3.1.1-6, and Table 12-8 below. Neutrophil (%) increased a mean (SD) of 12.7% (SD 14.1) in lithium participants and increased 0.7% (SD 6.8) in placebo participants from baseline to LOCF. Baseline values were similar in both groups with mean (SD) of 46.5% (SD 13.1) and 46.4% (SD 9.8) in lithium and placebo groups, respectively. Lymphocyte (%) decreased mean (SD) of 12.0% (SD 11.7) in lithium participants with baseline values of 42.0% (SD 10.9) while increased 1.4% (SD 10.6) from baseline values of 38.7% (SD 11.8) in placebo participants.
Table 12-8
Efficacy Phase - Change from Baseline to LOCF for Hematology Laboratory Values of Interest by Efficacy Phase Treatment Received Group.
Change in white blood count over the course of the Efficacy Phase is shown in Figure 12-1. The lithium participants increased 1.45 (×103/μL) while placebo participants decreased an average of 0.11 (×103/μL) at LOCF. Results below show the mean and SE of mean (SEM) change in WBC.
Figure 12-1
Efficacy Phase - Change in WBC (×103/μL) During the Efficacy Phase by Efficacy Phase Treatment Received Group. Note: Change score is week value minus baseline value, baseline is defined as the first visit of Efficacy Phase.
Results of the chemistry draws are reported in Tables 14.3.3.2.1 1-26, Figures 14.3.1.7-8 and Table 12-9. Lithium participants reported a mean (SD) increase of 53 (SD 71) U/L in alkaline phosphatase from baseline to LOCF while placebo participants reported a decrease of 10 (SD 35) U/L. Magnesium levels increased 0.22 (SD 0.25) mg/dL in lithium participants and decreased 0.03 (SD 0.12) mg/dL in placebo participants over the course of the study. Creatinine clearance (mL/min/1.7m2) was 133 (SD 37) in lithium participants and 130 (SD 35) in placebo participants at baseline and 124 (SD 36) and 134 (SD 38) in lithium and placebo participants at LOCF, respectively. Lithium participants decreased 10 (SD 25) and placebo participants increased 2 (SD 27) from baseline to LOCF.
Table 12-9
Efficacy Phase - Change from Baseline to LOCF for Serum Chemistry Laboratory Values of Interest by Efficacy Phase Treatment Received Group.
Thyroid panel results are reported in Tables 14.3.3.3.1 1-5 and Table 12-10. Changes in thyroid stimulating hormone during the Efficacy Phase are reported in Figure 12-2 below. Mean baseline values are 2.1 (SD 1.2) mIU/L in the lithium group and 1.9 (SD 0.9) mIU/L in the placebo group. At LOCF, lithium participants increased 3.0 (SD 3.1) while placebo participants had no change in mean value.
Table 12-10
Change from Baseline to LOCF for Thyroid Panel Laboratory Values of Interest During Efficacy Phase.
Figure 12-2
Efficacy Phase - Change in TSH (mIU/L) During the Efficacy Phase by Efficacy Phase Treatment Received Group. Note: Change score is week value minus baseline value, baseline is defined as the first visit of Efficacy Phase.
Total T3 (ng/dL) and Total T4 were similar in both lithium (change of −9.0, SD 33.2 in T3 and −0.4, SD 2.1 in T4) and placebo (change of −9.4. SD 26.8 in T3 and −0.5, SD 1.1 in T4).
Laboratory urinalysis results are reported in Tables 14.3.3.4.1 1-8 and coagulation measurements are in Tables 14.3.3.5.1 1-3.
12.2.5. Vital Signs, ECG and Physical Examinations
12.2.5.1. Physical Examination
Physical examination was completed at each office visit; for the Efficacy phase, this included Day 1 (used as the baseline value) and weeks 1-8. After protocol amendment 5, week 5 and 7 office visits were changed to phone calls and physical examinations were no longer completed.
Change in weight Z score throughout the Efficacy Phase is shown in Figure 12-3. Lithium participants experienced a 0.05 SD increase in weight Z score (using LOCF) and placebo participants increased 0.01 SD in weight.
Figure 12-3
Efficacy Phase - Change in Weight Z Score During the Efficacy Phase by Efficacy Phase Treatment Received Group. Note: Change score is week value minus baseline value, baseline is defined as the first visit of Efficacy Phase.
Height Z score decreased by 0.04 SD in the lithium treated participants and increased by 0.02 SD in the placebo treated participants from baseline to LOCF. Height values at LOCF were not available for 3 lithium participants and 5 placebo participants.
BMI measurements Table 12-11 were available at baseline and at Week 8/LOCF. At baseline, 25 (47%) of the lithium participants and 14 (50%) of the placebo participants were either overweight or obese (≥85th percentile when adjusted for age and sex). At Week 8/End-of-Phase visit 25 (50%) of the lithium participants and 11 (48%) of the participants measured were classified as overweight or obese.
Table 12-11
Efficacy Phase - BMI Classification.
Heart rate changed little over the phase, with a mean (SD) of 81 (16) and 79 (13) in lithium and placebo participants at baseline and 82 (15) and 78 (13) at LOCF respectively.
Blood pressure measurements were recorded for each participant at each weekly office visit. Mean (SD) systolic blood pressure Z score at baseline was 0.47 (1.01) for the lithium group and 0.93 (1.21) for the placebo group. At the End-of-Phase visit (LOCF) the mean (SD) Z scores were 0.46 (1.21) and 0.68 (1.21) for the lithium and placebo groups respectively. Change (from baseline to LOCF) in systolic blood pressure Z score was −0.01 SD (1.00) in the lithium group and −0.25 SD (0.96) in the placebo group. Diastolic blood pressure Z score at baseline was 0.41 (0.86) and 0.10 (0.68) and at LOCF was 0.41 (0.88) and 0.40 (0.89) for the lithium and placebo groups, respectively. Change from baseline to LOCF was-0.00 (1.03) in the lithium group and 0.30 (0.99) in the placebo group.
12.2.5.2. Electrocardiogram
Seventy-four of the 81 randomized participants completed an ECG at the end of the Efficacy Phase or at study phase termination. No investigators reported clinically significant findings for any participants. Twenty-two percent (11/50) lithium-treated participants and 25% (6/24) of the placebo-treated participants that completed an ECG had an investigator determination of “abnormal but not clinically significant.” Remaining ECGs were determined to be normal. ECG results for the Efficacy Phase are summarized in Table 14.3.5.1.
12.2.6. Other Safety Evaluations
12.2.6.1. Neurologic Rating Scale
The Neurological Rating Scale was completed at Screening Phase, Efficacy Phase Day 1 and weekly through Week 8.
Weekly results of the Neurological Rating Scale during the Efficacy Phase are presented in Table 14.3.6.1. Overall, 93% of the Neurological Rating Scales scored 0. One lithium participant [▬] scored a 4 at baseline; a 10 at Week 7 (3 for shoulder shaking, 1 for elbow rigidity, 4 for glabella tap, 1 for tremor and 1 for stiffness) and a 5 at Week 8. All other forms scored 3 (in 2 participants at baseline) or lower.
12.2.6.2. Columbia Suicide Severity Rating Scale
At each in-office visit of the Efficacy Phase, the Columbia Suicide Severity Rating Scale was completed. Table 14.3.7.1.1 summarizes suicidal behaviors and Table 14.3.7.2.1 summarizes suicidal ideations. There were 3 actual suicidal attempts reported on the SSRS-C during the Efficacy Phase; all 3 participants were randomized to lithium. One participant ▬] had an actual attempt and an interrupted attempt between screening and randomization. This participant completed the Efficacy Phase. The other 2 participants [▬ with an actual attempt and an interrupted attempt at week 1 and ▬ with an actual attempt at week 4] terminated the study due to suicidal ideation. There was one additional interrupted attempt at Week 1 in a lithium participant [▬], who went on to complete the Efficacy Phase.
Suicidal ideation from the SSRS-C is reported in Table 14.3.7.1.2. At baseline, 1 participant [▬] reported ideation with intent to act but no specific plan. This participant completed all 8 weeks of the Efficacy Phase. One participant [▬] at Week 1 reported ideation with plan and intent and one participant [▬] reported ideation intent with no plan. These participants are discussed above. No participant reported ideation with plan and intent after week 1.
12.2.7. Conclusions - Acute Efficacy Phase (Safety)
These data provide evidence that acute treatment with lithium is generally well-tolerated. Of note, the safety profile of lithium in this patient population appears to be generally consistent to what has been previously described in adults over many decades.
It should also be noted that lithium was generally well-tolerated during this acute phase. The upward titration of lithium in this part of the clinical trial was generally more rapid than typically seen in practice. In addition, lithium was dosed towards maximally tolerated levels. Despite these two facts, there were only a few discontinuations to lithium-related adverse events.
12.3. Long Term Effectiveness Phase
12.3.1. Extent of Exposure
Of the 44 participants entering the Long-Term Effectiveness (LTE) phase, 23 (52%) completed all 24 weeks of the phase (Table 12-12). Fifty-nine percent of the children in 7-11 age stratum completed all 24 weeks and were in the phase for a median (range) of 23.7 (0.4 – 25.9) weeks.
Table 12-12
Study Week of Termination During the Long-Term Effectiveness Phase.
Forty percent of older children in the 12-17 age stratum completed all 24 weeks and were in the phase for a median 11.3 (0 – 25.4) weeks. Two participants terminated without coming back for the first weekly visit (1 in each age stratum). Participants who received lithium during the Efficacy Phase were on study in LTE phase a similar length of time as those participants who received placebo during the Efficacy Phase, median (range) of 23.7 (2.1 - 25.4) and 23.6 (0 – 25.9), respectively. Table 12-12 summarizes the week of study termination by age strata and by Efficacy Phase treatment received. Data are summarized in the Long-Term Effectiveness Phase both by treatment received during the Efficacy Phase and by age strata at the start of the Long-Term Effectiveness Phase.
At the onset of the LTE Phase, participants receiving lithium during the Efficacy Phase were maintained at the same dose as the last visit of the Efficacy Phase. Participants who received placebo were titrated to lithium. Summary of daily lithium dose is in Table 12-13 below.
Table 12-13
Summary of Lithium Total Daily Dose (mg/kg/day) During the Long-Term Effectiveness Phase.
Lithium levels were drawn at Weeks 1, 2, 4, 6, 8, 12, 16, and 20, and at Week 24/phase termination. Table 12-14 summarizes the last reported lithium level for each group: participants randomized to lithium in the Efficacy Phase had a median value of 0.9 mEq/L with a range of 0.0 −1.9 mEq/L and participants randomized to placebo had a median 0.7 (0.0 – 1.3) mEq/L at the last LTE Phase draw. The summary statistics of each participant’s last 4 lithium levels are also reported.
Table 12-14
Summary of Last Reported Lithium Level During the Long-Term Effectiveness Phase.
12.3.2. Adverse Events and Tolerability
12.3.2.1. Summary of Treatment Emergent Adverse Events
A summary of TEAEs occurring during the LTE Phase is shown in Table 12-15, Table 12-16, and Tables 14.3.1.1.2A & B. Overall, there were 357 adverse events reported in 38 of the 44 safety participants (86%). The rate of TEAEs across the Efficacy Phase treatment arms was 90% for the lithium arm and 80% for placebo. The rate of TEAEs was similar in each age stratum: 86% for age 7-11 years and 87% for age 12-17 years. Mean number of AEs per participant was 8.1 during this phase. Six participants did not report any TEAEs during the LTE Phase, this included 2 participants that terminated without any office visits.
Table 12-15
LTE Phase - Overall Summary of Tolerability by Efficacy Phase Treatment Received Group.
Table 12-16
LTE Phase - Overall Summary of Tolerability by Age Strata.
The maximum severity of any TEAE was mild for 13 (30%) or moderate for 21 (48%) of the participants. Three participants treated with lithium during the Efficacy Phase reported severe adverse events, and one lithium participant reported a life-threatening event. The life-threatening AE was a suicide attempt which lead to study termination and is described below. The severe AEs included one participant ▬] with severe constipation, abdominal pain, and dizziness (reported on the same day); one participant [▬] with severe hair loss (probably related to study medication); and one participant [▬] reporting severe suicidal self injury (which led to study termination).
Twenty-two (76%) of participants treated with lithium and 10 (67%) of participants treated with placebo during the Efficacy Phase reported AEs as possibly, probably, or definitely related to study drug during the LTE Phase.
The maximum severity of any TEAE was severe or life-threatening in 1/29 (3%) of participants 7-11 years of age and in 3/15 (20%) of participants 12-18 years of age at the start of the LTE Phase. The 5 participants that had AEs considered definitely related to study medication all were in the 7-11 year age stratum.
12.3.2.2. Analysis of Adverse Events
12.3.2.2.1. Most Frequently Reported Treatment-Emergent Adverse Events
Table 12-17 summarizes the most frequently reported TEAEs (≥ 10% of the participants) reported during the LTE Phase. These results are similar to the AEs seen in the Efficacy Phase lithium treatment group. Overall, headache was the most frequently reported TEAE, with 30 events occurring in 18 (41%) of the 44 participants. GI disorders of nausea, vomiting, upper abdominal pain, diarrhea, and abdominal pain were also frequently occurring TEAEs. Nausea and vomiting were each present in 34% of the participants.
Table 12-17
LTE Phase - Most Frequently Occurring (≥ 10% of the Participants) Treatment-Emergent Adverse Events by Efficacy Phase Treatment Received Group and by Age Strata.
Other frequent TEAEs included rash (23%), tremors (18%), thirst (16%), pollakiuria (16%), enuresis (11%), and increased appetite (11%). All AEs of increased appetite occurred in the older (12-17 years) age stratum.
12.3.2.2.2. Treatment-Emergent Adverse Events by Intensity
There was 1 life-threatening AE ▬] in the LTE Phase: a suicide attempt, and the participant terminated from the study. There were 5 severe TEAEs in 3 participants: 1 participant [▬] experienced hair loss that was probably related to study therapy; 1 participant [▬] reported abdominal pain, constipation, and dizziness on the same day, not related to study therapy; and 1 participant ▬] was hospitalized for suicidal self injury, not related to study therapy and terminated from the study.
There were 77 (22%) moderate TEAEs of the 357 reported TEAEs. Twenty-one participants reported a maximum TEAE severity of moderate.
Of the 357 TEAEs, 274 (77%) were of mild severity, with 30% of participants reporting mild as the highest severity.
12.3.2.2.3. Treatment-Emergent Adverse Events by Relationship
Eight TEAEs were considered to be “definitely” related to study medication. These 8 TEAEs were reported in 5 (11%) of the 44 participants. These AEs included 7 gastrointestinal complications (3 nausea, 2 vomiting, 1 abdominal pain, and 1 abdominal discomfort) and 1 tremor.
There were 70 (20%) of the 357 TEAEs considered to be “probably” related to study medication, including 12 vomiting AEs and 9 nausea AEs. Of the 357 reported TEAEs during the LTE phase, 111 (31%) were “possibly” related and 168 (47%) were “unrelated”.
12.3.2.2.4. Listing of Adverse Events by Participant
A complete listing of all AEs is provided in Appendix 16.2.
12.3.2.2.5. Deaths, Serious Adverse Events and Adverse Events Leading to the Discontinuation of Study Medication
12.3.2.2.5.1. Deaths
There have been no participant deaths in this study.
12.3.2.2.5.2. Serious Adverse Events
There have been 2 SAEs reported in 2 participants during the LTE Phase as summarized in Table 14.3.1.5.2. All SAEs are reported as unrelated to study medication. The SAEs were suicide attempt [▬] and suicidal self injury [▬], both required hospitalization and both participants terminated from the study. Both participants received lithium during the Efficacy Phase and both were in the 12-17 year age stratum. These SAEs occurred at 8.4 weeks and 6 weeks of the LTE Phase.
12.3.2.2.5.3. Adverse Events Leading to the Discontinuation of Study Medication
Three participants had TEAEs that led to study termination:
- Participant [▬] had a life-threatening suicide attempt at 59 days into the LTE Phase that led to hospitalization and the participant was later terminated due to this event. This SAE is described above.
- Participant [▬] had suicidal self injury at 42 days into the LTE Phase that led to hospitalization and study termination. This SAE is described above.
- Participant [▬] reported vomiting of moderate severity, probably due to study medication at day 15 of LTE Phase and terminated from the study.
Two additional participants reported TEAEs that temporarily stopped study medication: [▬] for vomiting and [▬] for gastroenteritis.
12.3.3. Concomitant Therapy
12.3.3.1. Concomitant Medications
Concomitant medications taken during the LTE Phase are reported in Table 14.3.2.1.2A and 14.3.2.1.2B. The most commonly used medication was paracetamol (acetaminophen), which was used in 20 (46%) of the participants (35% of the participants in the 7-11 year age stratum and 67% of the participants in the 12-17 year age stratum). Six (14%) participants used amoxicillin during this phase, and it is the only other medication used in >10% of the participants. All participants using amoxicillin were in the 7-11 year age stratum. Use of paracetamol and amoxicillin during the LTE Phase was similar between Efficacy Phase treatment arms. Ibuprofen was not used in any participants during the LTE Phase.
12.3.3.2. Concomitant Psychotropic Medications
Concomitant psychotropic medications are summarized in Tables 14.3.2.2.2A, 14.3.2.2.2B and Table 12-18 below. Seventy-seven percent (34/44) of the participants used at least 1 concomitant psychotropic medication during the LTE Phase. Methylphenidate was used in 18 (41%) of the participants, and was the most frequently prescribed psychotropic medication during the LTE Phase. It was used in 55% of the 7-11 year and 13% of the 12-17 year old participants; it was used in 48% of the Efficacy Phase lithium treated participants and 27% of the placebo treated participants. Hydroxyzine was used in 13 (30%) participants, equally distributed between age strata and Efficacy Phase treatments. Also used in >10% of the participants were quetiapine, valproate sodium, lorazepam and lamotrigine.
Table 12-18
LTE Phase - Most Frequently Occurring (≥10% of the Participants) Concomitant Psychotropic Medications.
12.3.3.3. Concomitant Psychotherapy
Eighteen (41%) participants received concomitant psychotherapy during the LTE Phase: 52% of the Efficacy Phase lithium-treated participants; 20% of the placebo-treated participants; and 45% in the 7-11 age stratum and 33% in 12-17 age stratum. The most common type of therapy was behavioral therapy in 7 participants, with 3 additional participants receiving behavioral/cognitive therapy (listed under “other therapy”). Therapy types are summarized in Table 14.3.2.3.2A by age strata and 14.3.2.3.2B by Efficacy Phase randomized treatment group.
12.3.4. Clinical Laboratory Evaluations
Baseline visit of the LTE Phase is defined as the last visit of the Efficacy Phase. Laboratory measurements were completed at baseline, week 4, week 8, week 16 and week 24/end-of-phase.
Hematology results are shown in Tables 14.3.3.1.2 1-15; Figures 14.3.2, 1A-6A & 1B-6B; .and Table 12-19.
Table 12-19
LTE Phase - Change from Baseline to LOCF for Hematology Laboratory Values of Interest by Efficacy Phase Treatment Received Group and by Age Strata.
Change in white blood count over the course of the LTE Phase is shown below in Figure 12-4. The participants entering the phase on lithium had a mean baseline value of 8.45 (×103/μL) and decreased by a mean of 0.43 (×103/μL) while participants entering the phase on placebo had a baseline mean value of 6.03 (×103/μL) and increased an average of 0.72 (×103/μL) at LOCF. Participants in the 7-11 year age stratum and 12-17 year age stratum had a similar mean change in WBC at LOCF, 0.23 and −0.60 ×103/μL, respectively. Results below show the mean and SEM change in WBC.
Figure 12-4
LTE Phase - Change in WBC (×103/μL) During the LTE Phase by Efficacy Phase Treatment Received and by Age Strata. Note: Change value is week value minus baseline value, baseline is defined as the last visit of Efficacy Phase.
Participants randomized to lithium in the Efficacy Phase had a mean (SD) baseline neutrophil value of 60.0% (SD 9.2) and increased by mean (SD) of 0.6% (SD 9.2) while participants randomized to placebo had a baseline value of 47.4% (SD 10.0) and increased 9.9% (SD 9.3) at LOCF. Baseline Lymphocyte values in lithium participants were 29.1% (SD 8.7) and mean (SD) increase of 0.2 (SD 9.2) in lithium participants and baseline value of 40.0% (SD 9.6) with a decrease of 9.7% (SD 7.5) at LOCF in placebo participants that were tapered to lithium
Results of the chemistry draws are reported in Tables 14.3.3.2.2 1-26: “A” Tables are by age strata and “B” Tables are by Efficacy Phase treatment arm. Box-whisker plots of baseline values, LOCF, and change values for chemistry measurements of interest are presented in Figures 14.3.2 7-8 A (by age strata) and B (by Efficacy Phase treatment group); change values for these measurements are reported below in Table 12-20.
Table 12-20
LTE Phase - Change from Baseline to LOCF for Chemistry Laboratory Values of Interest by Efficacy Phase Treatment Received Group and by Age Strata.
Participants entering the phase on lithium reported a mean (SD) increase of 1 (SD 25) in creatinine clearance from baseline to LOCF while participants entering the phase on placebo reported a mean decrease of 12 (SD 21) mL/min/1.7m2. In the Efficacy Phase, a similar drop is noted in participants randomized to lithium who had a 10 (SD 25) mL/min/1.7m2 drop in creatinine clearance from baseline to the LOCF visit (participants randomized to placebo had a mean 2 (SD 27) increase in creatinine clearance.
Thyroid panel results are reported in Tables 14.3.3.3.2 1-5 A&B. Box-whisker plots of baseline values, LOCF, and change values for thyroid panel measurements of interest are presented in Figures 14.3.2 9-13 A (by age strata) and B (by Efficacy Phase treatment group), change values for these measurements are reported below in Table 12-21.
Table 12-21
LTE Phase - Change from Baseline to LOCF for Thyroid Panel Laboratory Values of Interest by Efficacy Phase Treatment Received Group and by Age Strata.
Changes in thyroid stimulating hormone are shown in Figure 12-5 below. In participants entering the phase on lithium, the mean (SD) TSH value at Baseline is 5.6 (SD 3.0) mIU/L and 1.8 (SD 0.6) mIU/L in the placebo group. At LOCF, lithium participants decreased to 4.3 (SD 2.7) mIU/L while placebo participants increased to 4.6 (SD 2.6) mIU/L. Mean (SD) change in the participants entering the phase on lithium was −1.5 (SD 3.5) and for participants entering on placebo was 2.8 (2.5). Little difference was seen between the age strata, with baseline values of 4.3 in both age groups. Change from baseline to LOCF in TSH was 0.0 (SD 3.0) mIU/L in 7-11 year olds and −0.3 (SD 5.1) mIU/L in 12-17 year old children.
Figure 12-5
LTE Phase - Change in TSH (mIU/L) During the LTE Phase by Efficacy Phase Treatment Received and by Age Strata. Note: Change score is week value minus baseline value; baseline is defined as the last visit of Efficacy Phase. TSH was only required at Week (more...)
Laboratory urinalysis results are reported in Tables 14.3.3.4.2 1-8 A&B and Laboratory Coagulation Measurements results are report in Tables 14.3.3.5.2 1-3 A&B.
12.3.5. Vital Signs, ECG and Physical Examinations
12.3.5.1. Physical Examination
Physical examination was completed at each office visit for the LTE Phase, this included Week 1 and every other week for Weeks 2-24. Weight, blood pressure, and heart rate were measured at each office visit; height and BMI were measured at the End-of-Phase visit only. These results are summarized in Table 14.3.4.2 A & B.
Change in weight Z score throughout the LTE Phase is shown in Figure 12-6 below. Baseline value is the last visit of the Efficacy Phase. Older children (12-17 age stratum) experienced a mean 0.12 increase in weight Z score (using LOCF) while younger participants (7-11 age stratum) decreased 0.04 in weight Z score. Changes (LOCF) were similar in participants in the Efficacy Phase lithium group (mean increase 0.01) and placebo group (mean increase 0.03).
Figure 12-6
LTE Phase - Change in Weight Z Score During the Long-Term Effectiveness Phase by Efficacy Phase Treatment Received Group and by Age Strata. Note: Change score is week value minus baseline value, baseline is defined as the last visit of Efficacy Phase. (more...)
Thirty-four participants used psychotropic medications during the LTE Phase; see Section 12.3.3.2. Change in weight Z score from baseline to LOCF increased 0.04 for the participants who received psychotropic medications and decreased 0.04 for participants not receiving psychotropic medications as seen in Table 12-22.
Table 12-22
LTE Phase - Change in Weight Z Score by Use of Psychotropic Medications.
Height Z score decreased by a mean of 0.07 in the 39 participants with LOCF measurements. Systolic blood pressure and diastolic blood pressure Z scores increased a mean of 0.14 and 0.18, respectively from baseline (last visit of the Efficacy Phase) to the last visit of the LTE Phase (LOCF). Baseline heart rate mean (82 beats per minute) did not change during the LTE phase.
BMI measurements (Table 12-23) are available at baseline and at Week 24/LOCF. At baseline, 22 (50%) of the participants are either overweight or obese (≥85th percentile when adjusted for age and sex). At Week 24/End-of-Phase visit 22 (56%) of the participants measured were classified as overweight or obese, with 5 participants missing BMI measurements.
Table 12-23
LTE Phase - BMI Classification.
12.3.5.2. Electrocardiogram
Thirty-nine of the 44 participants completed an ECG at the end of the LTE Phase or at study phase termination. No investigators reported clinically significant findings for any participant. Eight participants had an ECG with an investigator determination of “abnormal but not clinically significant”. Remaining ECGs were determined to be normal. ECG results for the LTE Phase are summarized in Table 14.3.5.2A and Table 14.3.5.2B.
12.3.6. Other Safety Evaluations
12.3.6.1. Neurologic Rating Scale
Results of the Neurological Rating Scale collected during the LTE Phase are presented in Table 14.3.6.2A & B. Overall, 96% of the Neurological Rating Scales scored 0. No participants scored higher than a 2 during the LTE Phase.
12.3.6.2. Columbia Suicide Severity Rating Scale
At each in-office visit of the LTE Phase, the Columbia Suicide Severity Rating Scale was completed. Table 14.3.7.2.1A & B summarizes suicidal behaviors and Table 14.3.7.2.2A & B summarizes suicide ideation. One participant [▬] reported suicidal behavior, at Weeks 4 and 6. [▬] reported an actual attempt, interrupted attempt, and self-injurious behavior at Week 4, and self-injurious behavior at Week 6. This participant terminated at Week 6 due to suicidal/homicidal ideation. There were no other reports of suicidal behaviors during this phase.
Suicidal ideation is present in 7 participants during the LTE Phase: Three participants had “wish to be dead” as the highest ideation. Two participants reported “non-specific active suicidal thoughts” as the highest ideation (one was at baseline visit only). One participant ▬] reported “ideation with any methods without intent to act” at Week 10 and one participant [▬] also reported “ideation with specific plan and intent” at Week 4. This participant terminated at Week 6 due to suicidal/homicidal ideation.
12.3.7. Conclusions - Long Term Effectiveness Phase (Safety)
Perhaps most noteworthy is the safety data from this phase. Lithium was well tolerated.
These data provide further evidence that lithium carbonate is generally tolerable in this patient population. What is noteworthy is that these data also provide information regarding the safety of lithium when it is combined with other commonly prescribed psychotropic agents in this patient population.
Reductions in renal function were not observed. There were few discontinuations from adverse events.
Reductions in thyroid function were expected in approximately 20% of the patient population (Gracious BL et al. JAACAP). When these elevations in thyrotropin occurred, these were readily manageable by the treatment algorithm that was in place such that thyroid dysfunction was not a major cause of study discontinuation.
12.4. Discontinuation Phase
12.4.1. Extent of Exposure
In Discontinuation Phase safety population, the participants are analyzed by the treatment actually received. Three of the COLT1 participants randomized to receive placebo actually received lithium and for the safety section, these participants are analyzed with the lithium participants. There are 31 participants in this phase, 17 (55%) treated with lithium and 14 (45%) treated with placebo.
Of the 31 participants entering the Discontinuation Phase, 13 (42%) completed the phase, 11 lithium treated participants and 2 placebo treated participants. Five participants terminated during the Discontinuation Phase (3 receiving lithium and 2 receiving placebo) and 13 participants had a mood relapse and entered the Restabilization Phase (3 lithium and 10 placebo). Participants receiving lithium completed a mean of 20.7 (SD 11.2) weeks while participants receiving placebo completed 8.7 (SD 8.5) weeks. Table 12-24 summarizes the duration on-study.
Table 12-24
Study Week of Termination During the Discontinuation Phase.
Participants randomized to placebo were tapered off lithium according the cross titration schedule in the protocol, Section 5.2.7. Median study dose at last visit of the phase was 1500 mg/day (range 600 to 2400 mg/day) and 28.7 mg/kg/day (range 16.0 to 40.6 mg/kg/day) for the lithium treated participants (Table 12-25).
Table 12-25
Summary of Study Drug Total Daily Dose (mg/kg/day) During the Discontinuation Phase.
Lithium levels were drawn at Weeks 1, 2, 4, 8, 12, and 16 and at Week 28 or End of Phase. Table 12-26 summarizes the last reported lithium level for each treatment group: the participants receiving lithium had a median value of 1.05 mEq/L with a range of 0.0 −1.53 mEq/L. Doses were not to be increased once the serum lithium level was >1.4 mEq/L. Participants receiving placebo had a median value of 0.0 mEq/L with a range of 0.0 −1.29 mEq/L. The placebo participant [▬] with the lithium level of 1.29 mEq/L received 10 days of lithium at week 6 and entered the Restabilization Phase at 7.4 weeks.
Table 12-26
Summary of Last Reported Lithium Level During the Discontinuation Phase.
12.4.2. Adverse Events and Tolerability
12.4.2.1. Summary of Treatment Emergent Adverse Events
A summary of TEAEs occurring during the Discontinuation Phase is shown in Table 14.3.1.1.3 and in Table 12-27). MedDRA coding for COLT1 AEs was reviewed and updated as needed to correspond to MedDRA version used for COLT2; see Appendix 16.4.2.1. Overall, there were 127 adverse events reported in 24 of the 31 safety participants (77%), with 88% of the lithium-treated participants and 64% of the placebo-treated participants reporting at least 1 TEAE. The lithium-treated participants reported a mean of 6.0 TEAEs per participant, while the placebo-treated participants reported a mean of 1.8 TEAEs.
Table 12-27
Discontinuation Phase - Overall Summary of Tolerability by Discontinuation Phase Treatment Received Group.
The maximum TEAE severity reported per participant was mild for 15 (48%) participants, moderate for 7 (23%) and severe for 2 (12%) participants. Both participants with severe TEAEs were treated with lithium (TEAEs described below in Section 12.4.2.2.2). The strongest relationship with study drug was unrelated in 7 (23%) participants, possibly related in 15 (48%) participants, and probably related in 2 (6%) participants. Both participants with a probable relationship to study medication were treated with lithium. These TEAEs are described below in Section 12.4.2.2.
12.4.2.2. Analysis of Adverse Events
12.4.2.2.1. Most Frequently Reported Treatment-Emergent Adverse Events
Table 12-28 summarizes TEAEs reported in ≥ 10% of the participants during the Discontinuation Phase. Overall, headache was the most frequently reported TEAE, with 19 events occurring in 10 (32%) of the 31 participants (6 lithium-treated and 4 placebo-treated participants). Upper abdominal pain was the second most frequently occurring TEAE with 14 events in 6 (19%) participants (5 lithium treated and 1 placebo treated). Initial insomnia was reported 6 times in 5 participants (3 lithium and 2 placebo). Enuresis had 11 occurrences in 4 (13%) participants (all lithium treated) and vomiting had 8 occurrences in 4 (13%) participants (all lithium treated). Decreased appetite also occurred in 4 (13%) participants (2 lithium and 2 placebo).
Table 12-28
Discontinuation Phase - Most Frequently Occurring (≥ 10% of the Participants) Treatment-Emergent Adverse Events by Discontinuation Phase Treatment Received Group.
12.4.2.2.2. Treatment-Emergent Adverse Events by Intensity
In the Discontinuation Phase, there were 3 severe TEAEs reported in 2 participants; both received lithium treatment. One participant [▬] reported enuresis, probably related to study medication, and the participant had dosing decreased. One participant [▬] reported difficulty concentrating and irritability, possibly related, and had study dose increased.
There were 15 (12%) moderate TEAEs of the 127 reported TEAEs. Seven (23%) participants reported a maximum TEAE severity of moderate: 3 lithium treated participants and 4 placebo treated participants.
Of the 127 TEAEs, 109 (86%) were of mild severity with 15 (48%) participants reporting mild as the most severe TEAE (10 (59%) lithium- and 5 (36%) placebo-treated participants).
12.4.2.2.3. Treatment-Emergent Adverse Events by Relationship
Three TEAE were considered to be “probably” related to study medication. These 3 TEAEs were reported in 2 (12%) of the participants, both received lithium. One participant reported hypothyroidism (mild severity) and one participant [▬] reported tremor (mild severity) and enuresis (severe severity).
Of the 127 TEAEs, 52 (41%) were considered “possibly” related to study medication: 44 occurred in lithium-treated participants and 8 occurred in placebo-treated participants. Of the 127 TEAEs, 72 (57%) were reported as “unrelated” to study medication. These included 54% (55/102) of the TEAEs reported in the lithium group and 68% (17/25) of the TEAEs reported in the placebo group.
12.4.2.2.4. Listing of Adverse Events by Participant
A complete listing of all AEs is provided in Appendix 16.2.
12.4.2.2.5. Deaths, Serious Adverse Events and Adverse Events Leading to the Discontinuation of Study Medication
12.4.2.2.5.1. Deaths
There were no participant deaths in this study.
12.4.2.2.5.2. Serious Adverse Events
There was 1 SAE reported during the Discontinuation Phase. Participant [▬] reported aggression on Discontinuation Phase day 18. This event was of moderate severity and possibly related to study medication. The participant received lithium treatment and was terminated from the study at day 18.
12.4.2.2.5.3. Adverse Events Leading to the Discontinuation of Study Medication
One lithium-treated participant had a TEAE that lead to study termination; participant [▬] reported aggression of moderate severity, possibly related to study medication. This led to discontinuation of study medication and the participant terminated due to adverse event.
12.4.3. Concomitant Therapy
12.4.3.1. Concomitant Medications
Concomitant medications taken during the Discontinuation Phase are reported in Table 14.3.2.1.3. The most commonly used medication was paracetamol (acetaminophen), which was used in 6 (19%) participants. Diphenhydramine hydrochloride was the second most commonly used concomitant medication (3 (10%) participants). All other medications were used in <10% of the population. One participant reported the use of ibuprofen, a prohibited medication.
12.4.3.2. Concomitant Psychotropic Medications
Concomitant psychotropic medications are summarized in Table 14.3.2.2.3, and were used during the Discontinuation Phase in 17 (55%) of the participants, including 8 (47%) of the lithium-treated participants and 9 (64%) of the placebo-treated participants. The most frequently used psychotropic concomitant medications were hydroxyzine in 5 (16%) of the participants and amphetamine sulfate in 4 (13%) of participants. Methylphenidate hydrochloride, quetiapine, and valproate semisodium were each used in 3 (10%) participants.
12.4.3.3. Concomitant Psychotherapy
Eleven (36%) participants received concomitant psychotherapy during the Discontinuation Phase, 5 (29%) lithium treated participants and 6 (43%) placebo treated participants. Cognitive therapy was used in 7 participants and behavioral therapy in 4 participants. Therapy types are summarized in Table 14.3.2.3.3.
12.4.4. Clinical Laboratory Evaluations
Baseline visit of the Discontinuation Phase is defined as the assessment taken at the last visit of the Long-Term Effectiveness Phase. Laboratory measurements were completed at baseline, at week 8, week 16, week 20 and week 28/end-of-phase. COLT2 Week 20 laboratory measurements were discontinued with Protocol Amendment 5.
Hematology results are shown in Tables 14.3.3.1.3 1-15 and Table 12-29. Note that by Week 8, only 3 placebo treated participants remain on-study.
Table 12-29
Discontinuation Phase - Change from Baseline to LOCF for Hematology Laboratory Values of Interest by Discontinuation Phase Treatment Received Group.
The mean (SD) change in white blood count from baseline to LOCF was 0.9 (SD 1.7) ×103/L in the lithium treated participants and −1.7 (SD 1.5) ×103/L in the placebo treated participants. Lithium treated participants had a 1.0 (SD 19.0) increase in neutrophils % while the placebo treated participants decreased 10.1 (SD 17.8) from baseline to LOCF. Lymphocytes % increased 1.3 (SD 18.1) in placebo participants and increased 5.9 (SD 12.4) in placebo participants. The changes in monocytes %, eosinophils % and basophils % were similar for lithium and placebo treated participants.
Change in white blood count over the course of the Discontinuation Phase is shown in Figure 12-7 below. The lithium participants increased an average of 0.9 (×103/μL) while placebo participants decreased an average of 1.7 (×103/μL) at LOCF. Results below show the mean and SEM change in WBC at each visit. Please note that by Week 8, only 3 placebo treated participants remain on-study and that Week 20 has a reduced sample size in COLT2.
Figure 12-7
Discontinuation Phase - Change in WBC (×103/μL) During the Discontinuation Phase by Discontinuation Phase Treatment Received Group. Note: Change value is week value minus baseline value, baseline is defined as the last visit of Long-Term (more...)
Results of the chemistry draws are reported in Tables 14.3.3.2.3 1-26, Table 12-30, and Figure 12-8. Mean change in creatinine was 0.0 (SD 0.2) in lithium-treated participants and 1.0 (SD 3.4) in placebo-treated participants. Mean decline in creatinine clearance was same in both treatment groups; −9 (SD 38) in lithium participants and −9 (SD 33) in placebo participants.
Table 12-30
Discontinuation Phase - Change from Baseline to LOCF for Chemistry Laboratory Values of Interest by Discontinuation Phase Treatment Received.
Figure 12-8
Discontinuation Phase - Change in Creatinine Clearance (mL/min/1.7m²) During the Discontinuation Phase by Discontinuation Phase Treatment Received Group. Note: Change value is week value minus baseline value, baseline is defined as the last visit (more...)
Thyroid panel results are reported in Tables 14.3.3.3.1 1-5 and Table 12-31 below.
Table 12-31
Discontinuation Phase - Change from Baseline to LOCF for Thyroid Panel Laboratory Values of Interest by Discontinuation Phase Treatment Received Group.
The mean (SD) change in TSH from baseline to LOCF was −0.6 (SD 1.6) mIU/L in the lithium treated participants and −2.9 (SD 2.4) mIU/L in the placebo participants. Total T3 decreased −0.2 (36.9) ng/dL in lithium participants and increased 6.5 (SD 23.0) ng/dL in the placebo participants.
Changes in thyroid stimulating hormone during the course of the Discontinuation Phase are reported in Figure 12-9 below. Baseline mean values are 5.1 (SD 3.2) mIU/L in the lithium group and 4.2 (SD 2.5) mIU/L in the placebo group. Because many placebo treated participants terminated the study early, their LOCF values are not captured in the Figure. Of the 14 placebo participants, 2 terminated without capturing lab values and 9 participants had the LOCF value before Week 8 (first scheduled lab visit), leaving only 3 participants with values collected at Week 8 or later. At LOCF, lithium participants decreased to a mean of 4.5 (SD 3.2) while placebo participants decreased to 1.6 (SD 0.6) mIU/L.
Figure 12-9
Discontinuation Phase: Change in Thyroid Stimulating Hormone (mIU/L) During the Discontinuation Phase by Discontinuation Phase Treatment Received Group. Note: Change value is week value minus baseline value, baseline is defined as the last visit of Long-Term (more...)
Laboratory urinalysis results are reported in Tables 14.3.3.4.3 1-8 and coagulation results are in Tables 14.3.3.5.3 1-3.
12.4.5. Vital Signs, ECG and Physical Examinations
12.4.5.1. Physical Examination
Physical examination was completed at each office visit of the Discontinuation phase, this included Weeks 1-4, 6, 8, 10, 12, 16, 20, and 24, and Week 28 or at End-of-Phase visit.
Change in weight Z score throughout the Discontinuation Phase is shown in Figure 12-10. Lithium treated participants experienced a 0.03 (SD 0.28) decrease in weight Z score (using LOCF) and placebo treated participants increased 0.04 (SD 0.14) in weight.
Figure 12-10
Discontinuation Phase - Change in Weight Z Score During the Discontinuation Phase by Discontinuation Phase Treatment Received Group. Note: Change score is week value minus baseline value, baseline is defined as the last visit of Discontinuation Phase. (more...)
Height Z score increased by a mean of 0.03 (SD 0.21) in the lithium treated participants and decreased by 0.13 (SD 0.23) in the placebo treated participants over the course of the phase (LOCF). LOCF height values were not available for 1 lithium participant and 2 placebo participants.
BMI measurements (Table 12-32) were available at baseline and at Week 28/LOCF. At baseline, 5 (29%) of the lithium participants and 9 (64%) of the placebo participants were either overweight or obese (≥85th percentile when adjusted for age and sex). At Week 28/end-of-phase visit, 4 (25%) of the lithium participants and 8 (67%) of the participants measured were classified as overweight or obese.
Table 12-32
Discontinuation Phase - BMI Classification.
Heart rate changed little throughout the phase, with a mean (SD) of 79.5 (SD 13.1) at baseline and 77.9 (SD 12.2) at LOCF.
Blood pressure measurements were recorded for each participant at each office visit. Mean (SD) systolic blood pressure Z score at baseline was 0.27 (1.04) for the lithium group and 0.57 (SD 1.02) for the placebo group. At the end-of-phase visit (LOCF), the mean (SD) Z scores were 0.32 (SD 1.09) and 0.67 (SD 0.97) for the lithium and placebo groups respectively. Change (from baseline to LOCF) in systolic blood pressure Z score was 0.05 (SD 1.04) in the lithium group and 0.10 (SD 1.38) in the placebo group. Diastolic blood pressure Z score at baseline was 0.31 (SD 1.05) and 0.23 (SD 0.74) and at LOCF was 0.21 (SD 0.78) and 0.60 (SD 0.71) for the lithium and placebo groups, respectively. Change from baseline to LOCF was −0.11 (SD 0.79) in the lithium group and +0.37 (SD 0.63) in the placebo group.
12.4.5.2. Electrocardiogram
Twenty-eight of the 31 randomized participants completed an ECG at the end of the Discontinuation Phase or at study phase termination. No investigators reported clinically significant findings for any participants. Twenty-five percent (7/28) of participants with an ECG completed, had an investigator determination of “abnormal but not clinically significant”. Remaining ECGs were determined to be normal (21/28). ECG results for the Discontinuation Phase are summarized in Table 14.3.5.3.
12.4.6. Other Safety Evaluations
12.4.6.1. Neurologic Rating Scale
The Neurological Rating Scale was completed at Discontinuation Phase Weeks 1-4, 6, 8, 10, 12, 16, 20, 24 and week 28 or at phase termination. Baseline visit is the last visit of the Long-Term Effectiveness Phase. Summary for Discontinuation Phase is reported in Table 14.3.6.3.
Results of the Neurological Rating Scale are presented in Table 14.3.6.3. Overall, 97% of the Neurological Rating Scales collected during the Discontinuation Phase scored 0. Only 1 participant [▬] reported non-zero scores: baseline score was 1, week 1 and week 2 scored 3, week 8, 12 and 20 scored 1 and week 24 scored 2. The participant completed the study with a score of 0 at week 28.
12.4.6.2. Columbia Suicide Severity Rating Scale
The Columbia Suicide Severity Rating Scale was completed at weeks 1-4, 6, 8, 10, 12, 16, 20, 24 and week 28 or phase termination. Table 14.3.7.3.1 summarizes suicidal behaviors and Table 14.3.7.3.2 summarizes suicidal ideation. No participants expressed any suicidal behaviors and 1 participant [▬] reported 1 episode of suicidal ideation (wish to be dead) at week 3. This participant entered the Restabilization Phase at week 5.
12.4.7. Conclusions – Discontinuation Phase (Safety)
Overall, lithium was generally well tolerated. TEAEs were similar to those reported in youths in the prior phases of this trial. In addition, the TEAEs were commensurate with the extant lithium literature in both pediatric and adult populations. Changes in laboratory values and other physiological measurements were consistent with previously reported results in adults. There were no new safety findings. Noteworthy was the modest impact of lithium on weight and creatinine. These findings suggest that over this length of exposure, lithium appears to have an overall acceptable safety profile.
12.5. Restabilization Phase
12.5.1. Extent of Exposure
The Restabilization Phase safety population includes 13 participants. Ten participants received placebo and 3 participants received lithium during the Discontinuation Phase; 5participants were in the 7-11 age stratum and 8 participants were in the 12-17 age stratum; 10 participants were from the COLT1 study and 3 participants were from the COLT2 study.
Of the 13 participants entering the Restabilization Phase, 9 (69%) completed all 8 weeks (Table 12-33) of the phase, see Section 10 for details of participant disposition. Participants completed a mean of 6.9 (SD 2.1) weeks.
Table 12-33
Study Week of Termination During the Discontinuation Phase.
Participants randomized to lithium in the Discontinuation Phase continued their Discontinuation Phase dose. Participants who received placebo during the Discontinuation Phase were titrated back to their effective dose at the end of the Long-Term Effectiveness Phase. Median dose was 1800 mg/day or 29.9 mg/kg/day at the end of the Restabilization Phase as shown below in Table 12-34.
Table 12-34
Summar of Lithium Total Daily Dose During the Restabilization Phase.
Lithium levels were drawn at Weeks 1, 2, 4, and 6, and at week 8 or End of Phase. Table 12-35 summarizes the last reported lithium level. Participants had a median lithium value of 1.10 mEq/L with a range of 0.70 −1.52 mEq/L.
Table 12-35
Summary of Last Reported Lithium Level During the Restabilization Phase.
12.5.2. Adverse Events and Tolerability
12.5.2.1. Summary of Treatment Emergent Adverse Events
A summary of TEAEs occurring during the Restabilization Phase is shown in Table 12-36. Overall, there were 36 adverse events reported in 10 of the 13 safety participants (77%). There was an average of 2.8 TEAEs per participant.
Table 12-36
Restabilization Phase: Overall Summary of Tolerability.
The maximum severity reported per participant was mild for 6 (46%) participants and moderate for 4 (31%). There were no severe TEAEs reported during this phase. The strongest relationship with study drug was unrelated in 4 (31%) participants and possibly related in 6 (46%) participants.
12.5.2.2. Analysis of Adverse Events
12.5.2.2.1. Most Frequently Reported Treatment-Emergent Adverse Events
Table 12-37 summarizes TEAEs reported in ≥ 10% of the participants during the Restabilization Phase. Consistent with the other phases, headache was the most frequently reported TEAE, with 7 events occurring in 4 (31%) of the 13 participants. Upper abdominal pain was the second most frequently occurring TEAE with 5 events in 3 (23%) participants.
Table 12-37
Restabilization Phase - Most Frequently Occurring (≥ 10% of the Participants) Treatment-Emergent Adverse Events.
12.5.2.2.2. Treatment-Emergent Adverse Events by Intensity
All of the 36 TEAEs reported in the Restabilization Phase were mild (n=29) or moderate (n=7). Six participants reported a maximum severity of mild, and 4 participants reported a maximum severity of moderate.
12.5.2.2.3. Treatment-Emergent Adverse Events by Relationship
Nineteen of the 36 TEAEs in the Restabilization Phase were considered to be unrelated to study medication, and 17 TEAEs were possibly related to study medication. The strongest relationship reported per participants was unrelated in 4 participants and possibly related in 6 participants. Three participants didn’t report TEAEs during this phase.
12.5.2.2.4. Listing of Adverse Events by Participant
A complete listing of all AEs is provided in Appendix 16.2.
12.5.2.2.5. Deaths, Serious Adverse Events and Adverse Events Leading to the Discontinuation of Study Medication
12.5.2.2.5.1. Deaths
There were no participant deaths in this study.
12.5.2.2.5.2. Serious Adverse Events
There were no SAEs reported during the Restabilization Phase.
12.5.2.2.5.3. Adverse Events Leading to the Discontinuation of Study Medication
There were no participants with a TEAE that lead to study termination during the Restabilization Phase.
12.5.3. Concomitant Therapy
12.5.3.1. Concomitant Medications
Concomitant medications taken during the Restabilization Phase are reported in Table 14.3.2.1.4. The most commonly used medication was paracetamol (acetaminophen) which was used in 6 (46%) participants. Diphenhydramine hydrochloride and cetirizine hydrochloride were each used by 2 participants. All other medications were used in <10% of the population.
12.5.3.2. Concomitant Psychotropic Medications
Concomitant psychotropic medications are summarized in Table 14.3.2.2.4 and were used during the Restabilization Phase in 8 (62%) of the participants. The most frequently used psychotropic concomitant medication was valproate semisodium used in 4 participants. Amfetamine sulfate, aripiprazol, hydroxyzine, and quetiapine were each used in 2 participants.
Four participants started new concomitant psychotropic medications during the Restabilization Phase. Three participants receiving placebo during the Discontinuation Phase started quetiapine, aripiprazole and divalproex sodium. All three completed the 8-week phase. One participant who received lithium during the Discontinuation Phase started divalproex sodium at 2 weeks and terminated at 2.9 weeks (lost to follow-up).
12.5.3.3. Concomitant Psychotherapy
Five participants received concomitant psychotherapy during the Restabilization Phase. Cognitive therapy was used in 3 participants and behavioral therapy in 2 participants. Therapy types are summarized in Table 14.3.2.3.4.
12.5.4. Clinical Laboratory Evaluations
Baseline visit of the Restabilization Phase is defined as the assessment taken at the last visit of the Discontinuation Phase. Laboratory measurements were completed at baseline, week 4 and week 8/end-of-phase.
Hematology results are shown in Tables 14.3.3.1.4 1-15 and measurements of interest are summarized in Table 12-38.
Table 12-38
Restabilization Phase - Change from Baseline to LOCF for Hematology Laboratory Values of Interest.
White blood count increased an average of 2.6 ×103/μL (SD 1.6) from baseline to LOCF, neutrophils increased a mean (SD) of 14.6% (16.0), lymphocytes decreased 5.7% (13.8) and monocytes decreased 0.5% (2.8) during the course of the Restabilization Phase.
Results of the chemistry draws are reported in Tables 14.3.3.2.4 1-26, summary of chemistry values of interest are reported in Table 12-39 below.
Table 12-39
Restabilization Phase - Change from Baseline to LOCF for Chemistry Laboratory Values of Interest.
Thyroid panel results are reported in Tables 14.3.3.3.4 1-5 and Table 12-40 below.
Table 12-40
Restabilization Phase - Change from Baseline to LOCF for Thyroid Panel Laboratory Values of Interest.
Thyroid stimulating hormone baseline mean (SD) values are 3.1 (SD 3.4) mIU/L and increase to 3.8 (SD 1.2) mIU/L at LOCF.
Laboratory urinalysis results are reported in Tables 14.3.3.4.4 1-8 and laboratory coagulation measurements results are summarized in Tables 14.3.3.5.4 1-3.
12.5.5. Vital Signs, ECG and Physical Examinations
12.5.5.1. Physical Examination
Physical examination was completed at each office visit for the Restabilization phase, this included Weeks 1-4, 6 and Week 8 or End-of-Phase visit. Tables 14.3.4.4 summarize results for heart rate, systolic blood pressure, systolic blood pressure Z score, diastolic blood pressure, diastolic blood pressure Z score, weight, weight Z score, height, height Z score, BMI, and BMI Z score. Height and BMI measurements were only done at baseline and End-of-Phase visits.
Change in weight Z score throughout the Restabilization Phase is shown in Figure 12-11. Participants experienced a 0.01 (SD 0.12) mean decrease in weight Z score (using LOCF) during the Restabilization Phase.
Figure 12-11
Change in Weight Z Score During the Restabilization Phase. Note: Change score is week value minus baseline value, baseline is defined as the last visit of Discontinuation Phase.
Height Z score increased by a mean of 0.06 (SD 0.17) over the course of the phase (LOCF). LOCF height values were not available for 2 participants.
BMI measurements Table 12-41 are available at baseline and at week 8/LOCF. At baseline, 6 (46%) of the participants are either overweight or obese (≥85th percentile when adjusted for age and sex). At Week 8/End-of-Phase visit, two participants are missing BMI (one healthy weight at baseline and one obese at baseline). In the change from baseline to LOCF, 1 overweight participant became a healthy weight and the other overweight participant became obese, resulting in 7 healthy weight participants and 4 obese participants.
Table 12-41
Restabilization Phase - BMI Classification.
Average increase in heart rate was 7.3 (SD 9.4) beats per minute over the phase, with a mean (SD) of 75.7 (SD 11.3) at baseline and 83.0 (SD 13.0) at LOCF.
Blood pressure measurements were recorded at each office visit. Mean (SD) systolic blood pressure Z score at baseline was 0.28 (SD 0.87) and at the end-of-phase visit (LOCF) the mean (SD) Z scores were 0.30 (0.67). Change (from baseline to LOCF) in systolic blood pressure Z score was 0.03 (SD 0.88). Diastolic blood pressure Z score at baseline was 0.37 (SD 0.76) and at LOCF was 0.55 (SD 0.62). Change from baseline to LOCF was 0.18 (SD 0.61).
12.5.5.2. Electrocardiogram
Eleven of the 13 participants completed an ECG at the end of the Restabilization Phase or at study phase termination. No investigators reported clinically significant findings for any participants. One participant had an investigator determination of “abnormal but not clinically significant”. Remaining ECGs were determined to be normal. ECG results for the Restabilization Phase are summarized in Table 14.3.5.4.
12.5.6. Other Safety Evaluations
12.5.6.1. Neurologic Rating Scale
The Neurological Rating Scale was completed at Restabilization Phase Weeks 1-4, 6 and Week 8 or at phase termination. Baseline visit is the last visit of the Discontinuation Phase.
Results of the Neurological Rating Scale are presented in Table 14.3.6.4. All of the Neurological Rating Scales collected during the Restabilization Phase scored 0.
12.5.6.2. Columbia Suicide Severity Rating Scale
The Columbia Suicide Severity Rating Scale was completed at Weeks 1-4, 6 and at Week 8 or phase termination. Table 14.3.7.4.1 summarizes suicidal behaviors and Table 14.3.7.4.2 summarizes suicidal ideation. No participants expressed any suicidal behaviors or suicidal ideation during the Restabilization Phase.
12.5.7. Conclusions – Restabilization Phase (Safety)
The interpretation of these safety data is limited by the small sample size. However, this information provides preliminary evidence to suggest that lithium can be safely re-initiated in young participants who have previously ended their treatment with lithium. In addition, it appears that lithium therapy may be both safe and effective when prescribed with other mood stabilizer treatments in the pediatric population. As previously stated, no new safety signals were noted.
12.6. Display of Treatment Emergent Adverse Events
Treatment-emergent AEs and SAE data are presented in the following tables:
- Overall Summary of TEAEs by Age Strata and/or Treatment Received for each phase individually in Section 14, 14.3.1.1.1 (Efficacy Phase), 14.3.1.1.2A & B (Long-Term Effectiveness Phase), 14.3.1.1.3 (Discontinuation Phase including COLT1) and 14.3.1.1.4 (Restabilization Phase including COLT1).
- TEAEs by MedDRA System Organ Class, and Preferred Term, Age Strata and/or Treatment Received for each phase individually in Section 14, Table 14.3.1.2.1 (Efficacy Phase), 14.3.1.2.2A & B (Long-Term Effectiveness Phase), 14.3.1.2.3 (Discontinuation Phase including COLT1) and 14.3.1.2.4 (Restabilization Phase including COLT1).
- TEAEs by MedDRA System Organ Class, Preferred Term, Intensity, Age Strata and/or Treatment Received for each phase individually in Section 14, Table 14.3.1.3.1 (Efficacy Phase), 14.3.1.3.2A & B (Long-Term Effectiveness Phase), 14.3.1.3.3 (Discontinuation Phase including COLT1) and 14.3.1.3.4 (Restabilization Phase including COLT1).
- TEAEs by MedDRA System Organ Class, Preferred Term, Relationship to Study Medication, Age Strata and/or Treatment Received for each phase individually in Section 14 Table 14.3.1.4.1 (Efficacy Phase), 14.3.1.4.2A & B (Long-Term Effectiveness Phase), 14.3.1.4.3 (Discontinuation Phase including COLT1) and 14.3.1.4.4 (Restabilization Phase including COLT1).
- Serious TEAEs by System Organ Class, Preferred Term, Age Strata and/or Treatment Received for each phase individually in Section 14, Table 14.3.1.5.1 (Efficacy Phase), 14.3.1.5.2A & B (Long-Term Effectiveness Phase), 14.3.1.5.3 (Discontinuation Phase including COLT1) and 14.3.1.5.4 (Restabilization Phase including COLT1).
- TEAEs that have led to discontinuation of study drug by Age Strata for each phase individually in Section 14, Table 14.3.1.6.1 (Efficacy Phase), 14.3.1.6.2A & B (Long-Term Effectiveness Phase), 14.3.1.6.3 (Discontinuation Phase including COLT1) and 14.3.1.6.4 (Restabilization Phase including COLT1).
- TEAEs that have led to death by Age Strata and/or Treatment Received for each phase individually in section 14, Table 14.3.1.7.1 (Efficacy Phase), 14.3.1.7.2A & B (Long-Term Effectiveness Phase), 14.3.1.7.3 (Discontinuation Phase including COLT1) and 14.3.1.7.4 (Restabilization Phase including COLT1).
Individual patient data associated with TEAEs are listed in Section 16 as follows:
- All AEs (Appendix 16.2)
- All SAEs (Appendix 16.2)
- All AEs leading to study discontinuation (Appendix 16.2).
12.7. OVERALL CONCLUSION - SAFETY
These data provide strong evidence to support the assertion that lithium has an acceptable tolerability profile in this patient population. Overall, there were very few discontinuations across the entire protocol that related to lithium related adverse events.
Noteworthy is the observation that the adverse event profile in this trial detected no new safety signal when compared to what is known about the use of lithium in adults. Prior to conducting this work, there was concern that lithium might adversely affect renal function when prescribed beyond an acute treatment period. No negative impact of lithium on kidney function was seen overall in this population. No participant discontinued lithium due to reduced renal function. It was anticipated that in some participants thyrotropin elevation might be clinically relevant. However, in such instances thyroid dysfunction was readily and safely addressable. Lithium also was noted to have a relatively modest impact on weight gain. In addition, it appears that lithium might be safely prescribed to participants in combination with other commonly prescribed psychotropic agents that are frequently given to this participant group.
When considered together, lithium consistently demonstrated both acute- and long-term tolerability in this participant population.
- SAFETY EVALUATION - A Randomized, Double-Blind, Placebo Controlled Study of the ...SAFETY EVALUATION - A Randomized, Double-Blind, Placebo Controlled Study of the Efficacy of Lithium for the Treatment of Pediatric Mania Followed by an Open Label Long-Term Safety Period, Double-Blind, Placebo-Controlled Discontinuation Phase, and Open Label Restabilization Period (COLT2)
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