DSI: Joseph Saponaro

DOV

A Multi-Center, Open-Label, partially randomized, Standard of Care (SOC) -Controlled Study to Evaluate the Long-Term Safety (1 yr) of Bicifadine for the Treatment of Chronic Low Back Pain.

Sponsor: Dov Pharmaceutical, Inc) Protocol: DOV-075-022-US Phase 3
Lead CRA: Sabine Langer, Senior CRA
Medical Monitor: Dr. Fred Duncanson/201-336-3124/Fax: 336-3157/Cell: 201-304-1394/ FDuncanson@DovPharm.com
Site #: 586 Waivers: Dr. Stuart Apfel (Dov) 201-968-0980 Sapfel@DocPharm.com
CRO: CATO www.CATO.com 781-890-4477 x211
CRA: Najdat Ktishieh, MD, Pharmalink Research Inc., 813-994-2324, 813-205-1540 (Cell), NKtishieh@aol.com
Central Lab: Mayo 800-826-5561 Anderson.Eileen@Mayo.Edu
Drug: Bicifadine SR 400mgm BID (may decrease to 300 or 200 if not tolerated)
AEs: Sedation; Mydriasis; N/V; Euphoria Watch out for: HA, Insomnia, HTN, Tachycardia
M of Action: NMDA (N-Methyl-D-Aspartate) Receptor Antagonist & NE (Norepinephrine) and Serotonin (5- HTP) Reuptake Inhibitors
De Novo subjects randomized 25:6 ratio to Bicifadine 400 mgm BID vs SOC (Standard of Care) (may down titrate to 300 & 200 BID)
DOV will reimburse subjects for meds for SOC after subject brings in a receipt from the Pharmacy
Central IRB = Chesapeake
1550 Subjects/ 150 Sites = 11 Subjects per Site
EDC: Quick Study Capture by: www.ETrials.com 888-500-4247

IC
Men Age: 18 – 65
Mod – severe LBP (Class 1 or 2 -> Quebec Task Force Classification for Spinal Disorders (QTFC) requiring pain meds > 3 months
PSR-VAS Pain score 40 – 100 & Roland- Morris Disability Questionnaire (RDQ) -> 10 @ V2

EC
Any pain other than LBP that is mod – severe & radicular pain below the knee
No epidural corticosteroid within 1 month
No for 3 wks -> antidepressant, muscle relaxant, TENS, Chiropractic, Acupuncture
Taken an SSRI or SNRI within 3 months for depression from V2 (OK within 3 wks if given for Pain or Sleep)
Opioid or benzodiazepine within 2 wks of V2
No NSAIDs x 1 wk of Baseline Visit 2 (Ibuprofen & Tylenol ok within 60H of V2)
(ASA 325 mgm QOD ok)
CA x 5 yrs
W/C or any litigation
No within 2 wks of Baseline V2 ?antipsychotics, anti-Parkinsonian, opioids, SD, Catapress, Floroquinolones, Flagyl, Biaxin, Erythromycin, Anti-Fungals, B-Blockers, Ace-Inhibitors, Calcium Channel Blockers, Dextromethorphan, Coumadin, Viagra, Tagamet, PPIs, Theo, sedating antihistamines, Thyroid meds, Ticlid, Herbal Meds

V 1 D -21 (Wk -3) Lab, Screening, ICF, CPE, D/C Pain Meds, RTC V2 when labs available (May stay on Ibuprofen & Tylenol, but need to D/C 60 H before V2)
V 2 D 1 Lab Baseline, EKG, Randomization, VAS ? 40 & RDQ ? 10
V 3 W 1 Lab, +/- 1D
V 4 W 2 Lab, +/- 2D
V 5 M 1 (Wk 4) Lab, +/- 3D
V 6 M 2 Lab, +/- 4D
V 7 M 3 Lab, +/- 5D, EKG
V 8 M 4.5 Lab, +/- 5D
V 9 M 6 Lab, +/- 5D, EKG
V10 M 9 Lab, +/- 5D, EKG
V11 M 12 Lab, +/- 5D, EKG
V12 M 12.1 Lab, Post-Treatment 7D +/- 1D After Final Dose

Notes

Do subjects randomized to SOC have to stay on one specific Rx or can their Rx be adjusted as necessary? On P. 28, it says it's ok to be adjusted.
On P. 18 # 5, talks about No Opioids x 2 wks prior to Baseline (V2D1). The narcotics need to be off 2 wks prior to V2. But they can be re-started thereafter. With SOC they can have a narcotic or an SSRI/anti-depressant.
On P. 18 # 6, talks about No NSAID are within 1 wk baseline. Do they have to wash off all NSAIDs after V1 also? Tylenol & Advil are prohibited 60 hrs prior to Baseline Visit. How many days between V1 & V2? What is the window? Between 21 days & 60 hrs.
We are only doing De Novo Study and the Roll-Over one? No, just the de novo one.

DOV Pharmaceutical Announces Positive Phase II Results For Its Novel, Non-Narcotic Analgesic Bicifadine

Hackensack, NJ, August 7, 2002. DOV Pharmaceutical, Inc. (NASDAQ: DOVP) today announced positive efficacy and safety results for its Phase II clinical trial investigating its novel, non-narcotic analgesic, bicifadine, in the treatment of moderate to severe post-surgical dental pain. These data indicate that bicifadine is an effective analgesic as compared to placebo, with an efficacy at least equivalent to codeine. It has the advantage of being longer acting and not being a narcotic or having addiction potential.
This Phase II trial was a single dose, double blind, placebo-controlled study conducted in 750 male and female patients between the ages of 16 and 45. Three doses of bicifadine (200, 400, and 600 mg) and one dose of codeine (60 mg) were compared to placebo using as a primary endpoint measure the Summed Pain Relief and Intensity Difference (SPRID) score, a measurement tool that reflects the total analgesia produced over the entire six hour test period. Bicifadine, in a dose dependent fashion, produced a significant (p<0.002) overall increase in SPRID scores compared to placebo, and codeine did not. Time course analysis revealed that codeine did produce significant pain relief within one hour but not at two hours and thereafter. This short duration of action did not allow codeine to reach significance when analyzed over the entire six hour test period. Both 400mg and 600mg of bicifadine produced significant (p<0.01) time related increases in pain relief with a median latency for onset of significant pain relief within one hour. Maximal analgesic effects of bicifadine occurred in two to three hours and these effects were sustained for the balance of the six hour period. The mean maximal analgesic score for codeine was 2.6 compared to 2.7, 2.9 and 3.3 for 200, 400 and 600 mg of bicifadine, respectively. The scores for 200 and 400 mg bicifadine were comparable to 60 mg codeine, while those for 600 mg of bicifadine were significantly (p<0.01) greater.
Both codeine and bicifadine were safe and relatively well tolerated without producing any serious adverse events. Codeine (60 mg) and the 400 and 600 mg doses of bicifadine produced significantly (p<.05) more adverse events than placebo with the most frequently reported symptoms being nausea and emesis. Some interaction with the surgical procedure may have contributed to these side effects, since more than 13% of the placebo patients also displayed nausea and emesis, effects normally seen with this surgical pain model. Dr. Abraham Sunshine, an internationally recognized pain researcher who has consulted for DOV in the development of bicifadine, stated that, "These positive results clearly demonstrate the analgesic effects of bicifadine in a very well accepted pain procedure. As a result, bicifadine may indeed represent a new class of analgesic more efficacious than codeine in its ability to reduce moderate to severe dental pain, but without the abuse, tolerance, and addiction liability commonly associated with the narcotic analgesics."
"We are very pleased by these data and encouraged by the continued positive clinical results shown by bicifadine. Five earlier double blind, placebo controlled Phase II studies of bicifadine used an immediate release formulation and demonstrated statistically significant pain reduction comparable to or greater than positive controls such as codeine. The current Phase II study using a controlled release formulation has achieved an important milestone in the development of bicifadine," said Dr. Bernard Beer, president of DOV. He added, "We look forward to the continued development of bicifadine, including the initiation of the Phase III program pending our end-of-Phase II meeting with the FDA." Bicifadine is a chemically distinct molecule with a unique profile of pharmacological activity. It has two primary biochemical actions: It enhances and prolongs the actions of norepinephrine and serotonin by inhibiting the transport proteins that terminate their physiological actions. In addition, it interferes with the ability of glutamate to stimulate calcium entry into neurons; thus acting as an NMDA (N-Methyl-D-Asparate) Receptor Antagonist, similar to Namenda. Preclinical and clinical studies indicate that any of these individual actions or a combination may account for the analgesic properties of bicifadine. Bicifadine is not a narcotic and, in preclinical studies, it has been shown not to act at any opiate receptor. In animal models, bicifadine did not demonstrate abuse, addiction, or dependence potential. Bicifadine development prior to this study included seven Phase I clinical trials, and fourteen Phase II clinical trials, involving over 1,000 patients. DOV conducts a joint venture partnership with Elan Corporation plc (NYSE:ELN) to develop controlled release formulations of bicifadine for the treatment of pain.
Adverse Events: Sedation, Mydriasis, Nausea, Vomiting, Euphoria. Watch for: HA, Insomnia, HTN, Tachycardia