Protocol development was initiated in October 2002 () using the MTOPS design as a starting point for the Complementary and Alternative Medicines for Urological Symptoms (CAMUS) trial. Both phytotherapies were to be given at commonly used dosages: 100 mg daily for Pygeum africanum and 320 mg daily for Serenoa repens.
The two botanical products differed in color and odor. Developing placeboes that would mask the odor required each purveyor to test preparations with various additives. One of the firms also conducted a test to determine participants’ perception of whether or not they were given the product or placebo. Stability tests were required for the placeboes and botanical products. To avoid enhancing the odor of an agent by having multiple gelcaps in a bottle, the products were to be distributed in blister packs. Because of the difference in color and odor of the two agents, participants were to take two gelcaps, one for each phytotherapy (product or placebo) daily to mask the study.
As phytotherapies were not expected to benefit those with the most bothersome symptoms, the upper limit of the American Urological Association Symptom Index (AUASI) score for eligibility was lowered from 30 in MTOPS to 24 (). The age criterion was lowered to 45 years of age from 50 years of age in MTOPS to increase the generalizability and practicality of the trial results. Since most MTOPS participants who crossed over to invasive or medical therapy did so due to clinical progression of BPH, the primary endpoint in CAMUS was time to clinical progression of BPH or crossover to invasive or open-label therapy for BPH.
More controversial was whether or not to include an active comparator from one of the two classes of drugs used in the MTOPS study to aid in the interpretation of potentially negative results. If phytotherapies and the active comparator did not demonstrate efficacy, then the finding might be attributed to differences between the MTOPS and CAMUS study populations. There was a concern, however, that study participants interested in botanical therapies might be deterred from participation by the inclusion of a prescription medical therapy.
The Prostate Cancer Prevention Trial (PCPT) finding that finasteride was effective in reducing the incidence of prostate cancer, but that prostate cancer cases that occurred on finasteride were more aggressive [15
] eliminated 5-alpha reductase inhibitors from consideration as the active comparator, and an alpha adrenergic blocking agent was chosen. The addition of the active comparator arm required a substantial increase in the sample size and a supplier for the alpha blocker.
CAMUS was originally a four-arm study of Pygeum africanum, Serenoa repens, an alpha adrenergic blocking agent, and placebo designed to determine if either phytotherapy or the active comparator was superior to placebo in prolonging the time to clinical progression of BPH or crossover to invasive or open label therapy for BPH. The main intent was to evaluate each phytotherapy agent against placebo. There were no plans to compare the two phytotherapy agents, especially since doing so would require enlarging the sample size to adjust for an additional treatment comparison. The study was to enroll 3300 patients evenly distributed across the four treatment arms. Initiation of participant enrollment was delayed while NIH unsuccessfully sought a donor of the alpha adrenergic blocking agent. Ultimately, NIH obtained additional funds to purchase the alpha adrenergic blocking agent and its matching placebo.
Dissemination of Results from a Related Study
Shortly after funding was obtained for the active comparator and before CAMUS began enrollment, the results of the NIH-sponsored STEP (Saw palmetto Treatment for Enlarged Prostates) study, an investigator-initiated randomized, double-blind, placebo-controlled single institution clinical trial of a saw palmetto extract for reducing BPH-related symptoms were reported to the CAMUS investigators (). Two hundred twenty-five men ≥ 50 years of age with baseline AUASI scores ≥ 8 were randomized to Saw palmetto 160 mg twice a day or a matching placebo. Although well-tolerated, Serenoa repens
did not demonstrate any benefit over placebo with respect to change in AUASI at one year, the primary outcome measure [16
]. It was not clear if these results, which contradicted results of some previous trials, reflected chance or called into question the efficacy of at least this particular preparation of Serenoa repens
, the same preparation selected for use in CAMUS, at the standard dose. Because saw palmetto is more widely used in the U.S. than Pygeum africanum
, the funding agencies felt that any phytotherapy trial in BPH had to include saw palmetto so dropping the saw palmetto arm and proceeding with a 3-arm study was not an option.
The negative findings from two NCCAM-funded clinical trials of two complementary and alternative medicines had an impact on the CAMUS study. In a study of St. John’s wort for depression, it was speculated that its lack of efficacy might have resulted from inadequate dosing [17
]. The finding that three preparations of Echinacea were ineffective against the common cold [18
] was accompanied by an editorial that suggested that NCCAM was selecting “implausible agents” for study based on their popularity and recommended that the agency conduct clinical trials in treatments where there is knowledge-based evidence that there is a reasonable chance of efficacy [19
]. The funding agencies strongly encouraged the investigators to change the focus of the CAMUS study from evaluating long-term efficacy in preventing progression of LUTS to determining if there was a dose of either botanical product that could provide short-term (6-18 months) reduction of LUTS.
Dose-ranging Study Designs
With the study now focused on evaluating multiple doses of the two botanical products, two types of study designs were discussed: 1) an intrapatient dose escalation study in which study participants on the phytotherapy agents would receive escalating doses at 6-month intervals: saw palmetto at 320 mg, 640 mg, 960 mg daily or Pygeum africanum at 100 mg, 200 mg, and 300 mg, and 2) a fixed dose design in which participants were assigned to placebo or a dose level of one of the phytotherapies to be taken over 12 months. The intrapatient dose escalation design would address the question of whether either phytotherapy, at any dose, would provide short-term efficacy.
The investigators opted for the fixed dose design, because it would directly compare each dose level against placebo. There was considerable discussion about the number of dose levels to study for each product. It was unclear whether there was a need to re-evaluate the 320 mg daily dose that had been used in STEP, but including it would provide an opportunity to determine if the STEP results could be replicated. The purveyors expressed some concern about the higher doses since studies had not previously been conducted at these dose levels. To maintain masking would have required all participants to ingest 6 gelcaps daily. Concerns about participant adherence led to the decision to conduct separate studies for the two agents, each with four arms, placebo and 3 doses of a botanical product. Clinical centers would be randomly assigned to participate in the saw palmetto or Pygeum africanum trial.
Each trial was designed to detect a 3-point difference (with standard deviation of 6) between each dose level and placebo with respect to the change in AUA symptom score from baseline to 12 months, the same outcome measure used in STEP. To preserve an overall 0.05 two-sided significance level between the two studies, each with 4 arms, placebo and 3 phytotherapy dose levels, would have required 125 patients per arm for a total of 1000 patients. NIH informed the investigators that this sample size was not feasible with the remaining funds available for the study, and that the investigators should aim for a study with 600 patients.
Since the STEP results did not detect a 3 point difference in the change in the AUA symptom score between saw palmetto and placebo, it was suggested that the study be designed to detect a smaller difference of 2 points. Using the intrapatient dose escalation design with 3 dose levels and dose escalation at 6 month intervals, study duration for each participant would be 18 months. With this design, each study would have two arms and would require 332 patients to detect a 2 point difference (with standard deviation of 6) between the botanical product and placebo with respect to the change in AUA symptom score from baseline. Design characteristics of the intrapatient dose escalation study design varied from the fixed dose design in that the one-sided significance level of 0.05 was used in each study which allowed a lower difference between treatment arms with respect to the change in AUA symptom index to be detected with a smaller sample size.
Loss of Purveyors for Botanical Products
When the STEP results were published [16
], the accompanying editorial speculated that the lack of efficacy associated with Serenoa repens
might be attributed to the specific preparation used [20
], the same preparation planned for CAMUS. Shortly following the publication, the purveyor for saw palmetto withdrew support for the study. The purveyor for Pygeum africanum
was acquired by another firm and it, too, withdrew from the study.
A significant delay ensued as NIH decided to proceed with a study solely focused on saw palmetto and issued a new RFP for a supplier of saw palmetto. The saw palmetto product selected for use in CAMUS is an ethanolic extract of saw palmetto berries and differs from the saw palmetto product tested in the STEP trial, which was produced with a CO2 extraction process.
Final CAMUS Design
In the final design, CAMUS is a prospective, randomized, double-blind, multicenter, placebo-controlled clinical trial to determine if escalating doses of saw palmetto (320 mg, 640 mg, 960 mg daily) reduce LUTS over an 18-month period in comparison to placebo and whether there is sufficient short-term efficacy and tolerability to merit testing for long-term efficacy in a trial focused on the prevention of BPH progression. Its primary objective is to determine if escalating doses of Serenoa repens reduces the AUA symptom score compared to placebo over 72 weeks of treatment and is well tolerated. Secondary objectives are to determine if Serenoa repens has a beneficial effect on subjective global assessment; assess its impact on the BPH Impact Index, the Quality of Life item score from the IPSS, the nocturia item score from the IPSS, peak uroflow, post-void residual volume, prostate specific antigen (PSA) level, erectile and ejaculatory function, ICSmale Incontinence scale, Jenkins Sleep Dysfunction scale, and NIH Chronic Prostatitis Symptom Index and to assess its impact on complete blood counts, coagulation studies and basic blood chemistries. Because the saw palmetto arm uses doses higher than those commonly used, participants have their doses slowly increased at 24-week intervals and are evaluated for safety 4 weeks after each dosage level change. (Table 3) The frequency of hematology, serum chemistry and EKG testing was increased to occur every 12 weeks in response to the recommendation by the Food and Drug Administration’s review of the Investigational New Drug (IND) application.
Eligible participants () are randomized equally to one of two treatment arms within two AUASI-defined strata (8-15, 16-24): extract of Serenoa repens 320 mg once daily for 24 weeks (one gelcap); followed by 640 mg daily for 24 weeks (two gelcaps) followed by 960 mg daily for 24 weeks (three gelcaps) or placebo. To maintain masking, all participants take one gelcap daily for the first 24 weeks, two gelcaps daily during the second 24 weeks and three gelcaps daily during the next 24 weeks. Protocol treatment is discontinued if the participant develops unacceptable toxicity, or meets one of the protocol-defined reasons for treatment discontinuation: noncompliance, withdrawal of informed consent, investigator discretion, diagnosis of prostate or bladder cancer, crossover to invasive or open-label therapy for BPH, or death. The study was approved by the Data Safety and Monitoring Board, and is conducted under an IND held by the NIH.