Simvastatin Augmentation of Lithium Treatment in Bipolar Depression

NCT01665950 | Terminated Phase 2 Results DMC

• 1 other identifier: 2011P002545
• Study Type: interventional
• Target: 4
• Locations: 1 country
• Sites: 1

Brief Summary

Primary Aim: To estimate the antidepressant efficacy of simvastatin versus placebo as an adjunct to lithium, valproate, and/or other atypical antipsychotic therapy among individuals with bipolar I disorder in a nonpsychotic major depressive episode. Hypothesis: Simvastatin will be superior to placebo in improvement of depressive symptoms assessed by the Montgomery-Asberg Depression Rating Scale (MADRS).

Conditions

Bipolar Disorder

Outcome Measures

Primary Outcomes (1)

• Change in MADRS (4 Weeks)

  Change in Montgomery-Asberg Depression Rating Scale (MADRS) in simvastatin-treated epochs versus placebo-treated epochs

  Baseline vs week 4 (and, for placebo nonresponders in 1st 4 weeks, week 8 vs week 4)

Study Arms (3)

Simvastatin-Simvastatin

EXPERIMENTAL

Subjects will receive simvastatin in phase 1 (4 weeks) and phase 2 (4 weeks)

Drug: Simvastatin

Placebo->Simvastatin

EXPERIMENTAL

Placebo non-responders after the 1st 4 weeks will be re-randomized 1:1 to placebo or simvastatin for the next 4 weeks

Drug: Simvastatin; Drug: Placebo

Placebo-Placebo

PLACEBO COMPARATOR

Placebo nonresponders for the 1st 4 weeks will be re-randomized 1:1 to placebo or simvastatin for the subsequent 4 weeks

Drug: Placebo

Interventions

Simvastatin DRUG

The study uses the Sequential Parallel Comparison design (SPCD), with two 4-week phases: n=30 subjects are randomized 1:1 to simvastatin versus placebo add-on for 4 weeks, with the nonresponders re-randomized 1:1 for a further 4 weeks. The SPCD will allow us to pool data from both phases to estimate the simvastatin treatment effect. Subjects who respond in phase 1, and all subjects who receive simvastatin in phase 1, continue blinded treatment in phase 2 to preserve the blind, but only phase 1 results are analyzed. Dosage for simvastatin or matched placebo 20mg daily for 8 weeks.

Placebo->Simvastatin; Simvastatin-Simvastatin

Placebo DRUG

Subjects (n=15) are randomized to placebo add-on for 4 weeks, with the nonresponders re-randomized 1:1 to statin vs placebo for a further 4 weeks. Subjects who respond in phase 1 continue blinded treatment in phase 2 to preserve the blind, but only phase 1 results are analyzed. Dosage for simvastatin or matched placebo 20mg daily for 8 weeks.

Placebo->Simvastatin; Placebo-Placebo

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age 18-65
• written informed consent
• meets Diagnostic and Statistical Manual - IV (DSM-IV) criteria (by Structured Clinical Interview for DSM-IV (SCID-I/P)) for bipolar I disorder, current episode depressed
• Montgomery-Asberg Depression Scale (MADRS) score of at least 20 (i.e., moderate depression) and no greater than 34 (i.e., severe depression) at screen and baseline visit
• Young Mania Rating Scale (YMRS) score \< 12 at screen and baseline visit
• currently treated with a lithium preparation (carbonate or citrate) at stable dose for at least 4 wks with level \>0.4 and \<1.0; and/or valproate at stable dose for at least 4 wks at level \>60 and \<110; and/or other atypical antipsychotic at stable dose for at least 4 weeks (at least minimum FDA-labeled dose).

You may not qualify if:

• Psychotic features in the current episode, as assessed by YMRS item #8\>6
• felt by the study clinician to require inpatient hospitalization for adequate management
• more than 3 failed pharmacologic interventions in the current major depressive episode, exclusive of primary mood stabilizer
• current substance use disorder other than nicotine, by SCID-I/P
• pregnant women or women of child bearing potential who are not using a medically accepted means of contraception (to include oral contraceptive or implant, condom, diaphragm, spermicide, intrauterine device, tubal ligation, or partner with vasectomy)
• women who are breastfeeding
• serious suicide or homicide risk, as assessed by evaluating clinician
• other unstable medical illness including cardiovascular, hepatic, renal, respiratory, endocrine, neurological, or hematological disease, based on review of medical history, physical examination, and screening laboratory tests
• patients who have taken an investigational psychotropic drug within the last 30 days
• patients receiving additional anticonvulsant, antipsychotic, or antidepressant within 1 week prior to study entry
• patients requiring continued treatment with excluded medications (see below).
• Excluded medications: other statins, which could influence Wnt signaling; any other drug known to interact with simvastatin, including potent inhibitors/inducers of CYP3A4 such as itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, voriconazole, cyclosporine or danazol; gemfibrozil or other lipid-lowering drugs that can cause myopathy when given alone; amiodarone, ranolazine, verapamil, diltiazem, or amlodipine; niacin; digoxin; coumarin anticoagulants; colchicine; nefazodone; protease inhibitors including ritonavir, indinavir, nelfinavir, or saquinavir.
• Allowed: benzodiazepines and sedative-hypnotic agents if dosage has been stable for 2 weeks prior to study entry; thyroid or estrogen replacement provided dosage has been stable for 1 month; antidepressants, antipsychotics, and anticonvulsants provided dosage has been stable for 1 week prior to study entry.

Sponsors & Collaborators

• Massachusetts General Hospital: lead

Study Sites (1)

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

MeSH Terms

Conditions

Bipolar Disorder

Interventions

Simvastatin

Condition Hierarchy (Ancestors)

Bipolar and Related Disorders; Mood Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Lovastatin; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds

Limitations and Caveats

The study was terminated early because delays in study initiation and insufficient recruitment. Our statisticians have advised us that this analysis is uninformative as it represents the change for one individual in 2 of the three arms of the study.

Results Point of Contact

• Title: Dr. Roy Perlis
• Organization: Massachusetts General Hospital, Center for Quantitative Health

rperlis@partners.org

617-643-6310

Study Officials

• Roy H Perlis, MD, MSc

  Massachusetts General Hospital

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor of Psychiatry

Study Record Dates

• First Submitted: April 9, 2012
• First Posted: August 16, 2012
• Study Start: August 1, 2012
• Primary Completion: October 1, 2014
• Study Completion: October 1, 2014
• Last Updated: May 9, 2017
• Results First Posted: February 23, 2017

Record last verified: 2017-04

Locations

US (1)