The second Phase III study,
CONQUERwill study overweight and obese patients (BMI of 27-45) with serious co-morbidities, such as hypertension, dyslipidemia and type II diabetes. The Phase III program will also include a six-month confirmatory factorial study, known as
EQUATE, which will evaluate two dose levels of Qnexa, compared to both placebo and the individual constituents of the combination. The Phase III program will enroll approximately 4,500 subjects. The co-primary endpoints for the Phase III studies will be the mean percent weight loss from baseline and the proportion of patients who lose at least 5% of their body weight. In a Phase II trial, over 50% of patients on Qnexa experienced 10% or more total body weight loss in 24 weeks.
Qnexa is a proprietary therapeutic formulation and dosing regime that incorporates the active ingredients from two previously approved products with demonstrated weight loss properties: Topamax and Fastin. By combining the activity of each of these compounds, Qnexa simultaneously addresses
appetite and
satiety, the two main mechanisms that impact eating behavior. As such, Qnexa appears to induce significantly greater weight loss than either individual compound. Further, clinical trials conducted with Qnexa have demonstrated superior efficacy and a significantly improved adverse effect profile as compared to other therapeutic options.
VIVUS and Duke University conducted a 200-patient, double-blind, placebo controlled Phase 2 trial designed to examine the safety and efficacy of Qnexa. Findings from this study demonstrated:
1. Qnexa achieved significantly greater weight loss as compared to placebo and each of the product's active ingredients alone.
2. Qnexa achieved a placebo-adjusted weight loss of 20.1 pounds at week 24
3. This is nearly twice the weight loss achieved with a high dose of Sanofi-Aventis' Acomplia (rimonabant) at week 52 (10.6 pounds) in a similar group of patients
4. Weight loss with Qnexa had not plateaued at 24 weeks as has been observed with other obesity therapeutics in development
5. Qnexa was well tolerated as evidenced by the fact that only one patient (8%) dropped out of the Qnexa study arm. Drop out rates in obesity trials of this nature typically occur due to adverse effects or the perception that the therapy is not working
6. Similar trials of Acomplia and Arena Pharmaceuticals' APD356 reported significantly higher drop-out rates of 45% and 30%, respectively.
VIVUS is currently undertaking additional formulation development for Qnexa to increase the convenience of patient dosing. Ultimately, the final Qnexa formulation will offer once-a-day, oral dosing utilizing advanced sustained and controlled release technology which will provide precision release of each active ingredient in order to maximize efficacy and tolerability.
TOPAMAX®
(Topiramate)
1. Used for epilepsy and migraine prophylaxis.
2. Is associated with Weight Loss!
3. Available strengths: 15 mgm to 200 mgm (Top dose 400 mgm)
4. Study is using 54 – 108 mgm.
5. Side Effects:
a. Non-AG Metabolic Acidosis as it is a Carbonic Anhydrase Inhibitor
b. Glaucoma
c. Somulence & Fatigue
d. Dizzy
e. Anorexia/Nausea
Fastin
(Phentermine)
1. Upper type, anorectic or anorexigenic (stimulant similar to amphetamine) weight-loss pill/appititie suppresant associated with: HTN; Tachycardia, Jitteryness/Tremor, and Seizures.
2. Multiple brand names including: Adipex-P, Fastin, Ionamin, Obenix, Obephen, Oby-Cap, Oby-Trim, Panshape M, Phentercot, Phentride, Pro-Fast HS, Pro-Fast SA, Pro-Fast SR, Teramine, Zantryl.
3. Associated with VHD (Valvular Heart Disease).
4. PPH (Primary Pulmonary Hypertension) associated with MR (Mitral Valve Regurgitation).
5. Can cause Heart Attack or Stroke.
6. Potential Drug of Abuse. Addicting & Habit-Forming.
7. Withdrawal Reactions like Depression and Lethargy.
8. May impair Thinking or Reactions.
9. Doesn’t mix well with ETOH.
10. Causes dry skin.
11. Insomnia
12. Personality Changes like feeling hyperactive or irritable.
13. Meant to be used for a few weeks to help jump start a diet.
14. Usual starting dose is 30 mgm. (The study is using 7.5 – 15).
Info from BioPortfolio Website
Patients treated with Qnexa had a mean reduction of 10% for cholesterol and 16.2% for triglycerides, as compared to a reduction of 3.5% and an increase of 6.7%, respectively, for the placebo group. Baseline cholesterol and triglycerides were considered normal. Decreases in blood pressure as measured by the mean change from baseline at week 24 were also observed in the Qnexa group as compared to the placebo group. These findings suggest that Qnexa may improve certain metabolic risk factors in obese patients. Qnexa was well tolerated in this trial. Adverse events occurring in greater than 10% in the Qnexa arm as compared to placebo included
paresthesia (mild tingling of the extremities),
altered taste and
increased urinary frequency. There were no dropouts in the Qnexa arm due to serious or severe adverse events. Qnexa is a proprietary pharmaceutical treatment that incorporates low doses of active ingredients from two previously approved products (phentermine and topiramate). By combining the activity of each of these compounds, Qnexa simultaneously addresses excessive appetite and high threshold for satiety, the two main mechanisms that impact eating behavior.
Questions
1. Indemnification: The sponsor likes to be held harmless for acts of negligence that the PI commits that are solely the error of the treating physician. For example, if a PI treats a subject's UTI during a study and the patient suffers an injury from this, it is squarely the PI’s fault and it would not be proper for the sponsor to sustain an injury by being held liable for it. However, we are aware of a BP study where the PI followed the protocol and had the subject wash off their BP medication and suffer a stroke from the lack of the proper BP treatment. The sponsor forced the PI to use his medical malpractice insurance to satisfy the claim for medical malpractice. Clearly, this was an injustice as the PI was following the protocol precisely and even though it is unusual for a stroke to occur during wash out, it certainly does not immunize the subject from having a stroke. When a stroke occurs during wash out it is important that the sponsor take responsibility for the liability. This should be true of any injury ex officio of changing a subject’s treatment while following the protocol. If this drug causes respiratory depression, are you going to be fully liable?
2. Study Fully Populated Causing Premature Early Termination: As sites advertise for patients to become research volunteers, the people that are good enough to step forward to join, wash off of their existing treatment, come to our site and devote a significant amount of their time with blood draws, signing paperwork and allowing the experimental protocol to progress, should be guaranteed that the sponsor will not prematurely shut down the study because they have obtained the needed number of subjects. That is, it should be the sponsor’s responsibility to do the number crunching early enough not to allow subjects to sign consent and undergo early termination just because the study is now considered full enough. This is not ethical or in the patients best interest. All subjects who sign consent must be allowed to continue thru the protocol if they are continuing to fulfill criteria regardless of how many subjects are in the trial.
3. Reimbursement for Screen Failures: Sites are taking finincial risk in the name of enrolling only those subjects who will successfully complete the trial. Sponsors need to recognize that this significantly slows enrollment. When we see a subject who may qualify but then again may not, we would be hesitant to enroll in that study. Since the exclusivity clock starts clicking as soon as the drug is patented it is imperative that the studies are done as quickly as possible. Sites that are rewarded for each piece of work they legitimately perform will have to enroll better. Sites with too high screen failure rates can be turned off to ensure the proper motivation to enroll high quality subjects is present.
4. Initial Fasting Labs and Informed Consent: Many trials have visit one with fasting labs and signing informed consent on the same day. This is less desirable than having a visit one where the subject presents non-fasting for the purpose of signing the informed consent form and having the study discussed with them. The potential problem is with a diabetic. If a diabetic patient answers an ad and presents fasting for visit one, a research related procedure was done prior to signing the ICF (Informed Consent Form). They could get a low sugar reaction while driving to the site and suffer an MVA. They may also feel pressured to sign the ICF quickly as they know when the do so they will finally get something to eat. This can be most safely avoided by allowing subjects to sign the ICF on a pre-visit one or by writing protocols that don't have fasting labs as a visit one procedure. Although I understand V1 labs are non-fasting for this trial.
5. Recruitment: Too often recruitment is an oversight thought to be the sites problem dealt with at a time other than the beginning of the trial. It becomes the sponsor’s problem after many sites under enroll. Wise sponsors address recruitment up front at the investigator’s meeting and include recruitment agencies. One budget neutral solution is for the sponsor to push to make available an IRB approved ad for those using the central IRB at the very beginning of the trial. In addition use of centralized recruitment agencies like Pi and Acurian can very useful and cost effective. All our databases could be larger. A small minority of people step forward to become research subject volunteers. Planning for recruitment issues at the beginning is much better than catch up at the end.