What is an investigational drug?
An investigational drug is one that is under study and is not approved by the U.S. Food and Drug Administration (FDA) for sale in the United States. Medical research studies are conducted to evaluate the safety and effectiveness of an investigational drug. These research studies are also called clinical trials. Once an investigational drug has been proven safe and effective in clinical trials, FDA may approve the drug for sale in the United States.
What is censavudine?
Censavudine is an investigational drug that is being studied for the treatment of HIV infection.
Censavudine belongs to a class (group) of HIV drugs called nucleoside reverse transcriptase inhibitors (NRTIs).2 NRTIs block an HIV enzyme called reverse transcriptase. (An enzyme is a protein that starts or increases the speed of a chemical reaction.) By blocking reverse transcriptase, NRTIs prevent HIV from multiplying and can reduce the amount of HIV in the body.
Censavudine is similar in chemical structure to the FDA-approved NRTI stavudine (brand name: Zerit).
However, in vitro studies have shown that censavudine may be more effective than stavudine and may be less toxic than stavudine and other NRTIs.4-6 (In vitro studies are studies done in test tubes or other laboratory equipment and not on animals or humans.) Research in animals has shown that censavudine is not associated with kidney or bone toxicities.7
How are clinical trials of investigational drugs conducted?
clinical trials are conducted in phases. Each phase has a different purpose and helps researchers answer different questions.8
- Phase I trials: Researchers test an investigational drug in a small group of people (20–80) for the first time. The purpose is to evaluate its safety and identify side effects.
- Phase II trials: The investigational drug is administered to a larger group of people (100–300) to determine its effectiveness and to further evaluate its safety.
- Phase III trials: The investigational drug is administered to large groups of people (1,000–3,000) to confirm its effectiveness, monitor side effects, compare it with standard or equivalent treatments, and collect information that will allow the investigational drug to be used safely.8
In most cases, an investigational drug must be proven effective and must show continued safety in a Phase III clinical trial to be considered for approval by FDA for sale in the United States. Some drugs go through FDA’s accelerated approval process and are approved before a Phase III clinical trial is complete. After a drug is approved by FDA and made available to the public, researchers track its safety in Phase IV trials to seek more information about the drug’s risks, benefits, and optimal use.8
In what phase of testing is censavudine?
Censavudine has been studied in a Phase IIb clinical trial.2
What are some studies on censavudine?
Study Names: 2008-004810-29 (EUDRACT Number)
Participants: HIV-infected adults who had taken HIV medicines before entering the study (also called treatment-experienced) but who were off HIV medicines for at least 3 months.
Purpose: The purpose of this study was to look at the antiviral activity, safety, and drug properties of censavudine.
Study Design: Investigators looked at four different dose levels of censavudine (100, 200, 300, and 600 mg). Within each dose group, participants were randomly assigned to receive either censavudine or placebo once daily for 10 days. (A placebo is an inactive drug that is identical in appearance to the active drug being studied.) Censavudine was administered without any other HIV medicines (also called monotherapy).
- Significant reductions in viral load (the amount of HIV in a blood sample) were seen after 10 days of treatment with each of the censavudine doses studied.
- In terms of safety, there were no serious side effects or study drop-outs caused by censavudine treatment. More participants taking censavudine had a moderate-to-severe side effect than participants taking placebo.9-11
: AI467003; NCT01489046
: Multiple countries (global)
: HIV-infected adults who had never taken HIV medicines before entering the study (also called treatment-naive)
: The purpose of this study was to identify a safe and effective dose of censavudine for when censavudine is used in combination with the FDA-approved HIV medicines efavirenz (brand name: Sustiva) and lamivudine (brand name: Epivir).
: All doses of censavudine were given orally and once daily. Participants were randomly assigned to one of the following four groups:
- 100 mg of censavudine + efavirenz + lamivudine
- 200 mg of censavudine + efavirenz + lamivudine
- 400 mg of censavudine + efavirenz + lamivudine
- 300 mg of the FDA-approved nucleoside reverse transcriptase inhibitor (NRTI) medicine tenofovir disoproxil fumarate (tenofovir DF) + efavirenz + lamivudine
In addition to their active HIV medicines, participants in some of the censavudine groups were also given placebo tablets so that all participants in the censavudine groups took similar-looking tablets and the same number of tablets daily. (A placebo is an inactive drug that is identical in appearance to the active drug being studied.)
- After 24 weeks of treatment and continuing through 48 weeks of treatment, the higher doses of censavudine had a similar effectiveness at reducing viral load when compared to tenofovir DF.
- When compared to the tenofovir DF group, higher percentages of participants in the censavudine groups developed HIV mutations that caused drug resistance to the study medicines. (Drug resistance is when HIV mutates [changes form] and becomes insensitive to a drug that was previously effective.)
- In terms of safety, two serious side effects related to censavudine led to study drop-outs. One of the serious side effects involved skin rash and mouth and genital ulcers; the other serious side effect involved low platelet counts. Two serious side effects related to tenofovir DF also led to study drop-outs.12,13
What side effects might censavudine cause?
In the 10-day Phase IIa study (EUDRACT number 2008-004810-29) discussed under the previous question, the most common side effects that occurred in the censavudine groups were abdominal pain, swollen lymph nodes, nausea, headache, and fatigue.11
In the Phase IIb study (NCT01489046), participants in the censavudine groups had a smaller decline in bone mineral density than the participants in the tenofovir DF group. (Bone mineral density is a measurement of the amount of minerals, such as calcium, in an area of the bone.) There was a trend towards a build-up of limb and trunk fat with censavudine treatment, especially at the highest dose tested. Also, a slight increase in cholesterol was seen with censavudine treatment.14
Because censavudine is still being studied, information on possible side effects of the drug is not complete. As testing of censavudine continues, additional information on possible side effects will be gathered.
Where can I get more information about clinical trials studying censavudine?
More information about censavudine-related research studies is available from the AIDSinfo database of ClinicalTrials.gov study summaries. Click on the title of any trial in the list to see the ClinicalTrials.gov trial summary and more information about the study.
I am interested in participating in a clinical trial of censavudine. How can I find more information about participating in a clinical trial?
Participating in a clinical trial can provide benefits. For example, a volunteer participant can benefit from new research treatments before they are widely available. Participants also receive regular and careful medical attention from a research team that includes doctors and other health professionals. However, clinical trials may also involve risks of varying degrees, such as unpleasant, serious, or even life-threatening side effects from the treatment being studied.8
Your health care provider can help you decide whether participating in a clinical trial is right for you. For more information, visit NIH Clinical Research Trials and You.
- United States National Library of Medicine. ChemIDplus Advanced. http://chem.sis.nlm.nih.gov/chemidplus/rn/634907-30-5. Last accessed on November 13, 2015.
- National Institute of Allergy and Infectious Diseases (NIAID). NIAID ChemDB, HIV Drugs in Development. Available at: http://chemdb.niaid.nih.gov/DrugDevelopmentHIV.aspx. Last accessed on November 13, 2015.
- Clayden P, Collins S, Frick M, et al. HIV i-BASE/Treatment Action Group. 2015 Pipeline Report. Benzacar A, ed. July 2015. Page 16. Available at: http://www.treatmentactiongroup.org/sites/g/files/g450272/f/201509/2015%20Pipeline%20Report%20Full.pdf. Last accessed on November 13, 2015.
- Dutschman GE, Grill SP, Gullen EA, et al. Novel 4'-Substituted Stavudine Analog with Improved Anti-Human Immunodeficiency Virus Activity and Decreased Cytotoxicity. Antimicrob Agents Chemother. 2004 May;48(5):1640-6. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC400579/. Last accessed on November 13, 2015.
- Yang G, Dutschman GE, Wang CJ, et al. Highly selective action of triphosphate metabolite of 4'-ethynyl D4T: a novel anti-HIV compound against HIV-1 RT. Antiviral Res. 2007 Mar;73(3):185-91. Available at: http://www.ncbi.nlm.nih.gov/pubmed/17109975. Last accessed on November 13, 2015.
- Wang F, Flint O. The HIV NRTI BMS-986001 does not degrade mitochondrial DNA in long term primary cultures of cells isolated from human kidney, muscle and subcutaneous fat. Abstract presented at: 19th International AIDS Conference; July 22-27, 2012; Washington, DC. Abstract TUPE042. Available at: http://pag.aids2012.org/abstracts.aspx?aid=17957. Last accessed on November 13, 2015.
- Guha M, Pilcher G, Moehlenkamp J, et al. Absence of renal and bone toxicity in non-clinical studies of BMS-986001, a nucleoside reverse transcriptase inhibitor (NRTI) of human immunodeficiency virus (HIV). Abstract presented at: 19th International AIDS Conference; July 22-27, 2012; Washington, DC. Abstract TUPE041. Available at: http://pag.aids2012.org/abstracts.aspx?aid=16832. Last accessed on November 13, 2015.
- National Institutes of Health (NIH). NIH Clinical Research Trials and You. Available at:http://www.nih.gov/health-information/nih-clinical-research-trials-you. Last accessed on November 13, 2015.
- Cotte L, Dellamonica P, Raffi F, et al. A Phase-Ib/IIa Dose-Escalation Study of OBP-601 (4’-ethynyl-d4T, Festinavir) in Treatment-Experienced, HIV-1-Infected Patients. Abstract presented at: 50th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC); September 12-15, 2010; Boston, MA. Abstract H-933. Available at: http://www.abstractsonline.com/Plan/ViewAbstract.aspx?sKey=d89fb4da-4268-4d6b-88ee-4f4ebcd548de&cKey=74572456-29b9-410f-8a57-972c2b0676c3&mKey=%7b93AEED6A-54D4-4EF6-99BD-A9B3CE9FACD9%7d. Last accessed on November 13, 2015.
- Hwang C, Zhu L, Chan H, et al. Antiviral activity, exposure-response, and resistance analyses of monotherapy with the novel HIV NRTI BMS-986001 in ART-experienced subjects. Abstract presented at: 13th International Workshop on Clinical Pharamcology of HIV Therapy; March 16-18, 2012; Barcelona, Spain. Abstract O_06. Available at: http://regist2.virology-education.com/abstractbook/2012_3.pdf. Last accessed on November 13, 2015.
- Cotte L, Dellamonica P, Raffi F, et al. Randomized Placebo-Controlled Study of the Safety, Tolerability, Antiviral Activity, and Pharmacokinetics of 10-day Monotherapy with BMS-986001, a Novel HIV NRTI, in Treatment-Experienced HIV-1-Infected Subjects. J Acquir Immune Defic Syndr. 2013 Jul 1;63(3):346-54. Available at: http://www.natap.org/2013/HIV/Randomized_Placebo_Controlled_Study_of_the_Safety,.13.pdf. Last accessed on November 13, 2015.
- Bristol-Myers Squibb. A Phase IIb Randomized, Controlled, Partially Blinded Clinical Trial to Investigate Safety, Efficacy and Dose-response of BMS-986001 in Treatment-naive HIV-1-infected Subjects, Followed by an Open-label Period on the Recommended Dose. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on December 7, 2011. NLM Identifier: NCT01489046. Available at: http://www.clinicaltrials.gov/ct2/show/NCT01489046. Last Accessed on November 13, 2015.
- Gupta SK, Lombaard J, Echevarria J, et al. HIV NRTI BMS-986001 in Antiretroviral-Naïve Subjects: Week 24/48 Analyses. 54th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC); September 5-9, 2014; Washington, DC. Levin: Conference reports for National AIDS Treatment Advocacy Project (NATAP); 2014. Available at: http://www.natap.org/2014/ICAAC/ICAAC_28.htm. Last accessed on November 13, 2015.
- McComsey GA, Gupta SK, Orrell C, et al. HIV NRTI BMS-986001 in Antiretroviral-Naïve Subjects: Evaluation of Bone and Metabolic Safety Data Through Week 48. 54th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC); September 5-9, 2014; Washington, DC. Levin: Conference reports for National AIDS Treatment Advocacy Project (NATAP); 2014. Available at: http://www.natap.org/2014/ICAAC/ICAAC_29.htm. Last accessed on November 13, 2015.
Last Reviewed: November 16, 2015