Drug Trial Snapshot: DIACOMIT

HOW TO USE THIS SNAPSHOT
The information provided in Snapshots highlights who participated in the clinical trials that supported the FDA approval of this drug, and whether there were differences among sex, race and age groups. The “MORE INFO” bar shows more detailed, technical content for each section. The Snapshot is intended as one tool for consumers to use when discussing the risks and benefits of the drugs.

LIMITATIONS OF THIS SNAPSHOT:
Do not rely on Snapshots to make decisions regarding medical care. Always speak to your health provider about the risks and benefits of a drug. Refer to the DIACOMIT Package Insert for complete information.

DIACOMIT (stiripentol)
dī-ə-ka-mət
Biocodex
Approval date: August 20, 2018

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DRUG TRIALS SNAPSHOT SUMMARY:

What is the drug for?

DIACOMIT is a drug used along with another drug (clobazam) to treat seizures in patients with Dravet syndrome who are 2 years of age or older. Dravet syndrome is a rare and severe form of epilepsy that starts in early childhood. It is associated with difficult to control seizures and various degrees of development disability.

How is this drug used?

The total daily dose of DIACOMIT is based on a patient’s weight, and it is then divided into two or three doses. DIACOMIT can be taken as a capsule or as a powder. DIACOMIT capsules should be swallowed whole with a glass of water during a meal. DIACOMIT powder is mixed in a glass of water and should be taken right away after mixing during a meal.

What are the benefits of this drug?

Patients with Dravet syndrome taking DIACOMIT along with other seizure medications experienced fewer seizures (generalized clonic or tonic-clonic type) than patients taking placebo with other seizure medications. In Trial 1, 71% of the patients taking DIACOMIT responded to treatment compared with 5% of the placebo group. In the second trial, 67% of the patients taking DIACOMIT responded to treatment and 9% to placebo. A patient was classified as a ‘responder’ if the number of seizures in the second month of treatment was at least 50% lower than the number in the month before treatment was started.

What are the benefits of this drug (results of trials used to assess efficacy)?

The table below summarizes efficacy results for the evaluated patients from clinical trials. The main trial endpoint was the percent of patients with a greater than 50% decrease in frequency of generalized tonic-clonic or clonic seizures in comparison to baseline period. The mean change from baseline in frequency of generalized clonic or tonic clonic seizures was also evaluated.

Table 1. Efficacy Results in the Intent-to-Treat Population in Trial 1 and Trial 2

	Trial 1                         N=41		Trial 2  N=23
	DIACOMIT N=21	Placebo N=20	DIACOMIT N=12	Placebo N=11
Responder Analysis a
No of responders/total (Responder Rate) [95% CI]	15/21 (71%) [52% – 91%]	1/20 (5%) [0.0% – 15%]	8/12 (67%) [40% – 93%]	1/11 (9.1%) [0.0%– 26%]
p-value b			0.0094
Percentage Change from Baseline in Seizure Frequencyc
n	20	16	11	9
Mean ± SD	-69% ± 42%	7.6% ± 38%	-74% ± 27%	-13% ± 62%
Median	-91%	7.4%	-81%	-27%
Min – Max	-100% – 28%	-75% – 65%	-100% – -33%	-87% – 140%
p-value d	0.0002		0.0056

^aResponder is defined as a patient with a greater than 50% decrease in frequency of generalized tonic-clonic or clonic seizures.

^b Fisher Exact Test

^c Frequency of generalized tonic-clonic or clonic seizures.

^d Wilcoxon Test

CI=confidence interval; SD=standard deviation.

DIACOMIT Prescribing Information

Were there any differences in how well the drug worked in clinical trials among sex, race and age?

• Sex: DIACOMIT worked similarly in males and females.
• Race: Data on race were not collected per local regulatory authorities.
• Age: Age groups were too small to allow a determination of whether there were any differences among them in how well the drug works.

Were there any differences in how well the drug worked in clinical trials among sex, race, and age groups?

The tables below summarize efficacy results by sex and age. Because of small sample sizes, these data should be interpreted with caution.

Table 2. Subgroup Analysis of the Primary Endpoint by Sex (Trial 1)

Sex	DIACOMIT	Placebo
Male
Responder, n (%)	5 (83)	1 (9)
Non-responder, n	1	10
Female
Responder, n (%)	10 (67)	0 (0)
Non-responder, n	5	9

Table 3. Subgroup Analysis of the Primary Endpoint by Age Group (Trial 1)

Age Group	DIACOMIT	Placebo
3-6 years
Responder, n (%)	4 (100)	0 (0)
Non-responder, n	0	6
6-9 years
Responder, n (%)	4 (66)	0 (0)
Non-responder	2	4
9-12 years
Responder, n (%)	2 (5)	1(2)
Non-responder, n	2	4
12-15 years
Responder, n (%)	5 (83)	0 (0)
Non-responder, n	1	2
≥ 15 years
Responder, n (%)	0 (0)	0 (0)
Non-responder, n	1	3

FDA Review

What are the possible side effects?

DIACOMIT may cause serious side effects, including excessive sleepiness, loss of appetite, weight loss, decrease in blood cell counts, and thoughts about suicide or dying.

The most common side effects of DIACOMIT are sleepiness, decreased appetite, agitation, ataxia (impaired balance or coordination), weight loss, low muscle tone, nausea, shaking, dysarthria (difficulty speaking words; difficulty forming words during speech), and insomnia (difficulty sleeping).

What are the possible side effects (results of trials used to assess safety)?

The table below summarizes adverse reactions in combined Trials 1 and 2 (safety population).

Table 4. Adverse Reactions in 5% or More of DIACOMIT-Treated Patients and More Frequently than on Placebo in Patients with Dravet Syndrome (Trial 1 and Trial 2)

Adverse Reactions	Trial 1 and 2 – Pooled Total
	DIACOMIT N=33 %	Placebo N=31 %
Gastrointestinal disorders
Nausea	15	3
Vomiting	9	0
Salivary hypersecretion	6	0
General disorders and administration site conditions
Fatigue	9	3
Pyrexia	6	3
Infections and infestations
Bronchitis	6	0
Nasopharyngitis	6	0
Investigations
Weight decreased	27	6
Weight increased	6	3
Metabolism and nutrition disorders
Decreased appetite	46	10
Nervous system disorders
Somnolence	67	23
Ataxia	27	23
Hypotonia	18	13
Tremor	15	10
Dysarthria	12	0
Psychiatric disorders
Agitation	27	16
Insomnia	12	7
Aggression	9	0

DIACOMIT Prescribing Information

Were there any differences in side effects among sex, race and age?

• Sex: The occurrence of side effects was similar in males and females.
• Race: Data on race were not collected per local regulatory authorities.
• Age: Age groups were too small to allow a determination of whether there were any differences among them in occurrence of side effects.

Were there any differences in side effects of the clinical trials among sex, race, and age groups?

The table below summarizes the occurrence of the most common adverse reactions by subgroup. Because of small sample sizes, these data should be interpreted with caution.

Table 5. Subgroup Analysis of Adverse Reactions by Sex (safety population)

Preferred Term	Sex	DIACOMIT (N=33) n/N1 (%)	Placebo(N=31) n/N1 (%)
Somnolence	Male	8/14 (57)	4/16 (25)
	Female	14/19 (74)	3/15 (20)
Anorexia	Male	8/14 (57)	1/16 (6)
	Female	7/19 (37)	2/15(13)

Clinical Trial Report

Table 6. Subgroup Analysis of Adverse Reactions by Age Group (safety population)

Preferred term	Age (years)	DIACOMIT (N=33) n/N1 (%)	Placebo (N=31) n/N1 (%)
Somnolence	1-6	4/7 (57)	4/7 (44)
	6-12	12/16 (75)	3/15 (20)
	12-17	6/10 (60)	0/3 (0.0)
	≥17	n/a	0/4 (0.0)
Anorexia	1-6	3/7 (43)	2/9 (22)
	6-12	7/16 (44)	0/15 (0)
	12-17	5/10 (50)	1/3 (33)
	≥17	n/a	0/4 (0)

Clinical Trial Report

WHO WAS IN THE STUDIES?

Who participated in the clinical trials?

The FDA approved DIACOMIT based primarily on evidence from two clinical trials (Trial 1 and Trial 2) of 64 patients with Dravet syndrome. Trial 1 was conducted in 15 centers in France and Trial 2 in 6 centers in Italy.

The demographics of these patients are presented below.

Figure 1 summarizes how many men and women were enrolled in the clinical trials.

Figure 1. Baseline Demographics by Sex (safety population)

FDA Review

Baseline Demographics by Race (safety population)

Data were not collected per local regulatory authority.

Figure 2 summarizes the percentage of patients by age in the clinical trials used to evaluate safety.

Figure 2. Baseline Demographics by Age (safety population)

FDA Review

Who participated in the trials?

The table below summarizes demographics of all patients in Trials 1 and 2 (safety population).

Table 7. Demographic Characteristics of Patients in the Combined Clinical Trials 1 and 2

Baseline Characteristic	DIACOMIT (N=33)	Placebo (N=31)	Total (N=64)
Sex (n, %)
Male	14 (42)	16 (52)	30 (47)
Female	19 (58)	15 (48)	34 (53)
Race – data not collected
Ethnicity-data not collected
Age (years)
Min-Max	3.0 – 16.7	3.2 – 20.7	3.0-20.7
Age Group (n, %)
1 to 6>	7 (21)	9 (29)	16 (25)
6 to 12>	16 (48)	15 (48)	31 (48)
12 to 17>	10 (30)	3 (10)	13 (20)
≥17 years	0 (0)	4 (13)	4 (6)
Geographic Region (n, %)
US	0 (0)	0 (0)	0 (0)
Europe	33 (100)	31 (100)	64 (100)

Adapted from FDA Review

How were the trials designed?

The benefits and side effects of DIACOMIT were primarily evaluated in two clinical trials. These trials enrolled patients with Dravet syndrome whose seizures were not well controlled on their current treatment, which included clobazam and valproate.

 

All enrolled patients used their current treatment for seizures for one month. After this baseline period, patients were randomly assigned to receive DIACOMIT or placebo two to three times a day in addition to their baseline treatment. Patients were then observed on that treatment for two months. Neither the patients nor the health care providers knew whether DIACOMIT or placebo was being given until after the trial was completed.

The benefit of DIACOMIT was evaluated by measuring the frequency of seizures (generalized clonic or tonic- clonic) as recorded by patients and/or their caregivers, using a diary and then comparing it to the frequency of seizures in placebo treated patients. The primary assessment of benefit was based on the percentage of patients who ‘responded’ to treatment. A patient was classified as a ‘responder’ if the number of seizures in the second month of treatment was at least 50% lower than the number in the month before treatment was started.

How were the trials designed?

The safety and efficacy of DIACOMIT were established in two randomized, double-blind, placebo-controlled trials. These trials enrolled patients with Dravet Syndrome aged 3 to 18 years who were inadequately controlled on clobazam and valproate, and who had at least 4 generalized clonic or tonic-clonic seizures per month despite optimized therapy.

During a 1-month baseline period, all enrolled patients continued to receive their optimized antiepileptic treatment. This period was followed by a 2-month treatment period. During the treatment period, patients were randomized to receive DIACOMIT (50 mg/kg/day) or placebo in addition to their current antiepileptic drug regimen.

The primary efficacy endpoint was the responder rate. A responder was defined as a patient who experienced a greater than 50% decrease in the frequency (per 30 days) of generalized clonic or tonic-clonic seizures during the double-blind treatment period compared to the 4 week baseline period (i.e., placebo run-in). The mean change from baseline in frequency of generalized clonic or tonic clonic seizures was also evaluated.

GLOSSARY

CLINICAL TRIAL: Voluntary research studies conducted in people and designed to answer specific questions about the safety or effectiveness of drugs, vaccines, other therapies, or new ways of using existing treatments.
COMPARATOR: A previously available treatment or placebo used in clinical trials that is compared to the actual drug being tested.
EFFICACY: How well the drug achieves the desired response when it is taken as described in a controlled clinical setting, such as during a clinical trial.
PLACEBO: An inactive substance or “sugar pill” that looks the same as, and is given the same way as, an active drug or treatment being tested. The effects of the active drug or treatment are compared to the effects of the placebo.
SUBGROUP: A subset of the population studied in a clinical trial. Demographic subsets include sex, race, and age groups.

PRESCRIBING INFORMATION

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