Three randomized controlled clinical trials have tested CVT-E002/COLD-fX for prevention of acute respiratory infection (ARI). Two of these, which are perhaps best classified as preliminary or phase 2 trials, were in elderly adults.14,15 The third, which can be classified as a confirmatory or phase 3 trial, tested COLD-fX among 323 adults aged 18 to 65.16
Table 1 (see page 11) provides a summary of these trials. All three of these found some evidence of preventive efficacy. Two small, unpublished and preliminary trials tested CVT-E002/COLD-fX for prevention of ARI and immune modulating effects in athletes.42
Acute Respiratory Infection Prevention Trials
1. McElhaney et al, 2006. A randomized, double-blind, placebo-controlled trial was conducted with 43 adults aged 65 or older who were in good health.14 Subjects were randomized to receive either 400 mg of COLD-fX (n = 22) or placebo (n = 21) each morning for 4 months. After 4 weeks of the study, subjects returned for a clinical visit during which they received a standard dose of influenza vaccine containing 15 mcg/mL of hemagglutinin for 3 vaccine strains (A/Johannesberg/82/96, A/Nanchang/933/95, and B/Harbin/07/94). Subsequent visits were at 8 and 16 weeks.
Subjects were asked to record if they experienced any of the following 8 symptoms: fever, sore throat, cough, nasal congestion, chills, headache, fatigue, or aches/pains. On the self assessment, they were asked to record the number of days they experienced each symptom, whether they felt the study medication helped reduce symptoms, and any adverse events. The primary outcome was self-reported incidence and duration of ARI symptoms.
Overall, results from the treatment group were not statistically distinguishable from those in the placebo group on both frequency and duration of ARI symptoms. However, a secondary analysis of the data suggested possible prevention effects during the last 2 months of observation. During these 8 weeks, 62% of the placebo group reported symptoms, compared with 32% in the COLD-fX group (p < 0.05). Also, during the last 8 weeks of the study, the duration of ARI-related symptoms was found to be 55% shorter in the COLD-fX group than in the placebo group (5.6 days vs. 12.6 days, p = 0.04). Participants did receive influenza immunization after one month of intervention. Although viral identification with either was not completed or reported, antibody response was measured and no significant difference was found between the treatments.
Symptomatic treatment, such as non-steroidal anti-inflammatory drugs (NSAIDs) were used by 5 (22.7%) subjects taking COLD-fX and 7 (33%) in the placebo group. One subject in the COLD-fX group and 3 subjects in the placebo group reported taking antibiotics for the ARIs. Treatment was well tolerated in both groups and rates of perceived side effects were nearly identical. Mild adverse events reported over the 16-week study included gastrointestinal complaints (nausea, heartburn and diarrhea), muscle and joint pain, and dry mouth. The trend towards decrease in ARI symptoms established in this small preliminary study encouraged further investigation.
2. McElhaney et al, 2004. A randomized, double-blind, placebo-controlled study was conducted during the 2000 and 2001 influenza seasons.15 This was originally planned as a single season study, but when first season infection rates were insufficient to test hypotheses, the trial was extended to a second year. The observation period was for 8 weeks in the first season and 12 weeks in the second season, so it is unclear whether this should be considered a single trial or a meta-analysis of two trials. Either way, the results can be interpreted as preliminary evidence of benefit.
Elderly nursing home and assisted living residents aged 60 years or older were recruited for the study. The average age of the subjects was 81 years for the first observation period (n = 89) and 83.5 years for the second observation period (n = 109) with 74% of the participants being women. Approximately 90% of the participants had received influenza vaccine in each of the 2 years of the study. Subjects were randomized to receive either 200 mg of COLD-fX extract (n = 97) or matched placebo (n = 101) 2 times daily. Seventy-eight subjects completed the first study and 103 subjects completed the second study.
Subjects were monitored twice weekly for signs and symptoms of acute respiratory infection (ARI). ARI was defined by the new onset of 2 symptoms: one respiratory symptom (cough, sore throat, nasal or sinus congestion, or runny nose) and one additional respiratory symptom or one constitutional symptom (feverishness, chills/sweats, myalgia, fatigue, headache, poor endurance, or increased shortness of breath).
When symptoms were identified, a viral throat or nasopharyngeal culture was performed and tested for the presence of influenza, RSV, parainfluenza, and rhinovirus. The primary outcome of the study was the incidence of clinically confirmed ARI. Secondary endpoints included severity of respiratory illness, duration of respiratory illness, laboratory-confirmed respiratory illness, severity of influenza illness, and duration of influenza illness.
Combining data from both seasons revealed 36 episodes meeting ARI case definition in the placebo group and 33 cases in the COLD-fX group. This small positive trend was not statistically significant. However, influenza culture (a secondary endpoint analysis) revealed 7 laboratory and symptom-confirmed cases of influenza in the placebo group versus only 1 case in the COLD-fX group (p = 0.03). Laboratory and symptom-confirmed ARI due to RSV was also lower in the COLD-fX group compared to placebo (p = 0.009).
Monitoring of adverse effects revealed no significant differences or meaningful trends in self-reporting or laboratory monitoring. While randomization appeared adequate, evidence of blinding was not presented. Adequate interpretation of pooled data analyses is limited by the changes in methods between the 2 seasons (e.g., 8-week vs. 12-week monitoring). Nevertheless, the apparent reduction in confirmed influenza infection is intriguing, and certainly sufficient to justify another larger randomized, double-blind, placebo-controlled trial that tests ability to prevent flu-like respiratory infection.
3. Predy et al, 2005. The most persuasive evidence of the effectiveness of COLD-fX in preventing ARI was reported in 2005. A randomized, double-blind, placebo-controlled (RCT) study recruited 323 subjects aged 18 to 65 who had contracted at least 2 colds in the past year.16 Subjects were randomized to 400 mg of COLD-fX (n = 153) or placebo (n = 170) daily for 4 months. Of these, 130 in the COLD-fX group and 149 in the placebo group completed the 4-month study. The published report of this Phase 3 clinical trial underwent rigorous peer review, and it was published in the Canadian Medical Association Journal. Reported methodology conforms to currently accepted standards for randomized controlled trials, and includes description of a priori power calculations, and methods for recruitment, enrollment, randomization, allocation concealment, symptom severity assessment and monitoring, and data management. Statistical methods were rigorous and included an intention-to-treat analysis. Blinding was adequately reported, including blinding of the statistician during most analyses. Success of patient blinding was tested by asking participants whether they thought they were given COLD-fX or placebo.
The primary outcome measure was the number of Jackson-verified colds per subject. Secondary measures included severity of symptoms (total symptom score), number of days symptoms were experienced, and duration of all colds during the 4-month treatment period. Subjects were asked to contact the study investigators at the onset of a cold. Subjects were asked to complete a daily log to document the severity of their cold-related symptoms (sore throat, runny nose, sneeze, nasal congestion, malaise, fever, headache, hoarseness, earaches and cough) on a 4-point scale (0 = no symptoms; 1 = mild symptoms; 2 = moderate symptoms; 3 = severe symptoms). The total symptom score was calculated by summing the daily scores for all symptoms. A 2-day total symptom score greater than 14 (modified Jackson criteria) was considered to indicate a Jackson-verified cold (the Jackson criteria are a well-established measure in common cold trials).
Results were positive and relatively consistent across measured outcomes. The mean number of colds per person was 0.68 in the COLD-fX group compared to 0.93 in the placebo group (p = 0.017). The number of subjects with 1 cold was 95 (64%) in the placebo group and 71 (55%) in the COLD-fX group—this difference did not reach statistical significance. However, the number of people with ≥ 2 colds was 34 (23%) in the placebo group compared to 13 (10%) in the COLD-fX group. This result was highly statistically significant (p = 0.004). For those with Jackson-defined colds, the average duration was 16.5 days in the placebo group and 10.8 days in the COLD-fX group (p < 0.001). The average total symptom score was 112.3 in the placebo group and 77.5 in the COLD-fX group (p = 0.002). These and other apparent benefits were consistent and statistically significant, hence unlikely to be due to chance.
Rescue medications such as NSAIDs were used by 26.2% and 29.5% of the subjects in the COLD-fX and placebo groups, respectively. Four subjects in the COLD-fX group and 5 in the placebo groups reported taking antibiotics for their colds and flu during the 4-month study period. Adverse effects were monitored in a standard and reasonable fashion and were statistically indistinguishable in the placebo and COLD-fX groups, with no meaningful trends suggestive of underlying risks. Baseline comparisons provided evidence of adequate randomization, as groups were equivalent at baseline. Adequacy of blinding was supported by the fact that 70% of those taking COLD-fX and 77% of those taking placebo indicated that they thought they were given the COLD-fX preparation. Limitations include lack of data on those who could not be reached for follow-up, and lack of generalizability to elderly populations. People over 65 and those who had received a flu shot in the previous 6 months were excluded, and were not represented in this trial.
4. McElhaney et al, 2001. An unpublished abstract from a study was presented at the First International Scientific Congress on Nutrition and Athletic Performance held in Alberta, Canada on August 10, 2001. The abstract described 2 studies: (1) a small, observational study in 1997 to 1998 in which athletes (professional hockey players) ingesting COLD-fX were questioned regarding perceived efficacy in preventing and relieving cold symptoms, and (2) a study conducted in 1998-99 in which blood samples were taken and lymphocytes challenged with 3 different strains of influenza virus and analyzed for TNF-α and IL-2.43 According to unpublished manuscripts supplied by CV Technologies, a group of 14 athletes took 400 mg per day of COLD-fX for the season. Eight of 14 respondents at mid-season reported feeling “less run down while on the road.” Of 12 respondents at the end of the season, there was a reported decrease in the incidence of ARI compared to the previous year. A second group of 8 athletes reported using the product acutely at the onset of ARI symptoms as follows: 3 capsules [600 mg] 3 times per day on day 1; 2 capsules [400 mg] 3 times per day on day 2; and 1 capsule [200 mg] 3 times per day on day 3. Seven athletes responded to a questionnaire. Five out of 7 reported that COLD-fX prevented their colds from developing and “made them feel better.” The only adverse event reported was diarrhea, which may or may not be attributed to the study medication.
The second study cited in the unpublished abstract compared the effect of 400 mg per day of COLD-fX in 18 athletes as compared to 19 athletes who served as controls. Compared to controls, lymphocytes challenged with influenza virus ex vivo were found to have a significantly greater IL-2 (p < 0.05) and TNF-α (p < 0.05) production.