Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT00140179 |
| Other study ID # |
BMHC-3658 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
Phase 3
|
| First received |
August 31, 2005 |
| Last updated |
November 23, 2009 |
| Start date |
September 2004 |
| Est. completion date |
May 2008 |
Study information
| Verified date |
November 2009 |
| Source |
Beersheva Mental Health Center |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
Israel: Israeli Health Ministry Pharmaceutical Administration |
| Study type |
Interventional
|
Clinical Trial Summary
Valproic acid is a leading mood stabilizer for the treatment of bipolar disorder. Its
well-known teratogenicity limits its use in young women of childbearing age. According to
toxicologic studies the teratogenicity of valproate stems from its free carboxylic group.
Valnoctamide is an isomer and an analog of valpromide. Unlike valpromide, valnoctamide does
not undergo a biotransformation to the corresponding free acid. It is also likely or at
least possible that valnoctamide is anti-bipolar. In mice valnoctamide has been shown to be
distinctly less teratogenic than valproate. An injection at day 8 of gestation produced only
1% exencephaly (as compared to 0-1% in control mice and 53% in valproate treated mice).
The investigators are performing a double-blind controlled trial of valnoctamide as an
anti-bipolar drug. If shown to be anti-bipolar, valnoctamide could be an important valproate
substitute for young women with bipolar disorder who are at risk of pregnancy. Patients
newly admitted to the Beersheva Mental Health Center may participate if they meet Diagnostic
and Statistical Manual of Mental Disorders - 4th edition (DSM-IV) criteria for mania or
schizoaffective disorder, manic type. Patients admitted to the study are treated with
risperidone at doses of the physicians' discretion beginning with 2 mg daily on days 1 and
2. Valnoctamide or placebo is begun at doses of 600 mg per day (200 mg three times daily)
and increased to 1200 mg (400 mg three times daily) after four days.
Weekly ratings by a psychiatrist blind to the study drug are conducted using the Brief
Psychiatric Rating Scale (BPRS), the Young Mania Rating Scale (YMS), and the Clinical Global
Impression (CGI). Weekly blood is drawn for drug levels of valnoctamide to be measured by
gas chromatography. Each patient receives valnoctamide or placebo for 5 weeks.
Low teratogenic mood stabilizers are a high priority for current research.
Description:
Valproic acid is a leading mood stabilizer for the treatment of bipolar disorder. Its
well-known teratogenicity limits its use in young women of childbearing age (1-3). The
alternative mood stabilizers such as lithium and carbamazepine also have teratogenic
potential so the treatment of bipolar disorder in young women is problematic. The
difficulties are particularly acute in those young women patients who respond well to
anti-bipolar therapy and maintain or begin normal interpersonal and marital relations and
desire to have children.
One approach to this problem has been the search for valproic acid derivatives with less
teratogenic potential (4). According to toxicologic studies the teratogenicity of valproate
stems from its free carboxylic group (2, 3). Valpromide is an amide derivative of valproate
without the suspect free carboxylic group. It was synthesized and marketed and has
anticonvulsant efficacy, at least as good as valproic acid (1). There are some reports of
its efficacy in bipolar disorder as well (5). In some animal species, only a small amount of
valpromide is metabolized to valproic acid. However, in humans valpromide is metabolized to
a large degree to valproic acid and so it does not solve the problem of teratogenicity (1,
6).
Valnoctamide is an isomer and an analog of valpromide. Unlike valpromide, valnoctamide does
not undergo biotransformation to the corresponding free acid (6-9). In animal studies it is
at least as anticonvulsant as valproate and valpromide (1, 6, 10). It has been marketed as
an anxiolytic and sedative in several European countries (as Nirvanil) including Italy,
Holland and Switzerland but has not actively been promoted as an anticonvulsant. It was
marketed in the USA as Axiquel by McNeil in the 1970's. Unfortunately, despite considerable
efforts we have not been able to obtain pharmacovigilance data from this period. Given its
equivalence to valproate and valpromide as an anticonvulsant in animal models of epilepsy
(1, 6, 10), it is reasonable to assume that valnoctamide is also anticonvulsant in humans.
It is also likely or at least possible that valnoctamide is anti-bipolar. In mice
valnoctamide has been shown to be distinctly less teratogenic than valproate (11). Injection
at day 8 of gestation produced only 1percent exencephaly (as compared to 0-1percent in
control mice and 53 percent in valproate treated mice). Embryolethality rates showed similar
results: 52 percent with valproate vs. 5percent in the controls and 2 percent with
valnoctamide.
Valnoctamide's patent is expired (12) and it is not the property of any major pharmaceutical
company. Pharmaceutical company support cannot be obtained for our trial; therefore it is
investigator initiated.
Valnoctamide will be synthesized for our study by Banyan Chemical in India (which has been
inspected by the FDA) by GLP (good laboratory practice) in a manner acceptable for human use
by the Israel Ministry of Health (and in principle for an IND by the FDA). Banyan
manufactures at the same site generic compounds, atenolol for instance, sold in the USA and
distributed by international companies, Novartis for instance.
Study Design:
The study has been submitted to our Helsinki Committee and only patients who give informed
written consent will be accepted. Patients newly admitted to the Beersheva Mental Health
Center may participate if they meet DSM-IV criteria for mania or schizoaffective disorder,
manic type. Minimal Young Mania Scale = 20. Only patients admitted to the hospital within
the previous 72 hours will be eligible for the study. Exclusion criteria will be as in
previous studies of mania with this design by our group (15-17) and will include drug abuse,
active physical illness, and of course pregnancy.
Patients admitted to the study will be treated with risperidone at doses of physicians'
discretion beginning with 2 mg daily on days 1 and 2. On days 3 and 4 the risperidone dose
could be increased to a maximum of 4 mg daily or decreased to 1mg daily. On days 5 to study
end the dose could be increased to a maximum of 6 mg daily or decreased to a minimum of 1mg
(see ref #18). Dose of risperidone will be a secondary outcome measure (see reference #15 &
#16). No washout from previous medication is required but patients who received depot
neuroleptics within the past 2 weeks or more than 300 mg of chlorpromazine equivalents in
the past three days will be excluded. Trihexyphenidyl (up to 4 mg daily) will be available
as necessary for extrapyramidal symptoms and benzodiazepines for sleep. Valnoctamide or
placebo will be begun at doses of 600 mg per day (200 mg three times daily) and increased to
1200 mg (400 mg three times daily) after four days. This dose is based on relative
anticonvulsant effects of valproate and valnoctamide in animal studies (1, 6, 10).
Patients will receive valnoctamide or identical capsules of placebo as assigned by the
control psychiatrist according to random order; manic and schizoaffective manic patients
will be randomized separately. Weekly ratings by a psychiatrist blind to the study drug will
be conducted using the Brief Psychiatric Rating Scale (BPRS), the Young Mania Rating Scale
(YMS), and the Clinical Global Impression (CGI). Primary outcome measure will be BPRS.
Weekly blood will be drawn for drug levels of valnoctamide to be measured by gas
chromatography (19). Each patient will receive valnoctamide or placebo for 5 weeks.
Power Analysis:
We have demonstrated significant effects as add-on in mania in this design with lithium
(15), carbamazepine (16), and phenytoin (17). Each study had an N of about 40 patients,
recruited over 18 months in each study. In each study as in the present proposal, a mood
stabilizer or potential mood stabilizer was added to haloperidol at doses of physician's
discretion for five weeks.
Lithium adds clinically and statistically significant benefit to haloperidol treatment of
mania (15) as does carbamazepine (16) and phenytoin (17). Such an "add-on" design is
consistent with clinical practice and makes sense since dopamine blockers and mood
stabilizers probably work by different mechanisms in mania. Valproate is typically used
clinically in acute mania as an add-on to neuroleptics as well. Three positive studies
published in excellent journals (15-17) from our group using this design are probably better
than formal power analysis, which depends on a range of assumptions that are collapsible
into the experience of our three studies. Because the prior probability of an effect of
valnoctamide is lower than that of the above well-known compounds, we suggest recruitment of
80 patients over 36 months to adequately power this study rather than the 40 patients in
each of our previous studies. Since valnoctamide is no longer patented, orphan drug
procedures or a use patent of the type granted to Abbott for divalproex sodium will be
necessary to make this drug available for bipolar patients at risk for pregnancy in the
future. An adequately powered study is therefore important at this stage.
References
1. Bialer M, Haj-Yehia A, Badir K, Hadad S: Can we develop improved derivatives of
valproic acid? Pharm World Sci 1994; 16(1):2-6.
2. Nau H, Headrick X: Valproic acid teratogenesis. ISI Atlas Sci Pharmacol 1987; 1:52-56
3. Nau H, Hauck RS, Ehlers K: Valproic acid-induced neural tube defects in mouse and
human: aspects of chirality, alternative drug development, pharmacokinetics and
possible mechanisms. Pharmacol Toxicol 1991; 69(5):310-21.
4. Bialer M: Pharmacokinetic considerations in the design of better and safer new
antiepileptic drugs. J Control Release 1999; 62(1-2):187-92.
5. Lemoine P, Fondarai J, Faivre T: Valpromide increases amplitude of heart rate circadian
rhythm in remitted bipolar and unipolar disorders. A placebo-controlled study. Eur
Psychiatry 2000; 15(7):424-32.
6. Bialer M: Clinical pharmacology of valpromide. Clin Pharmacokinet 1991; 20(2):114-22.
7. Bialer M, Haj-Yehia A, Barzaghi N, Pisani F, Perucca E: Pharmacokinetics of a
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Pharm Sci 1988; 77:831-834.
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hyperirritability. McNeil Laboratories Inc.
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teratogen. J Biol Chem 2001; 276(39):36734-41.
14. Shaltiel G, Shamir A, Belmaker RH, Greenberg ML, Agam G: Valproate inhibits inositol-P
synthase: mood stabilization by inositol depletion elaborated. submitted
15. Biederman J, Lerner Y, Belmaker RH: Combination of lithium carbonate and haloperidol in
schizo-affective disorder: a controlled study. Arch Gen Psychiatry 1979; 36(3):327-33.
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17. Mishory A, Yaroslavsky Y, Bersudsky Y, Belmaker RH: Phenytoin as an antimanic
anticonvulsant: a controlled study. Am J Psychiatry 2000; 157(3):463-5.
18. Yatham LN, Grossman F, Augustyns I, Vieta E, Ravindran A: Mood stabilisers plus
risperidone or placebo in the treatment of acute mania. International, double-blind,
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