Trial design

This was a Phase IIB (pivotal) clinical trial conducted in Nigeria by the National Institute for Pharmaceutical Research and Development (NIPRD) that compared the safety and efficacy of a phytomedicine derived from plants indigenous to Nigeria (Niprisan^®) in people with SCD (Wambebe 2001). The trial was double‐blind and randomised, with concealment of allocation. It was of cross‐over design, with each arm randomised to receive placebo or Niprisan^® for a total of six months. No washout period is clearly described. In only one of the references is such a period of one month mentioned. Although a period of one month is mentioned in the article in Current Therapeutic Research, it is not clear how this period of time was decided upon (Wambebe 2001). The protocol was approved by the National Agency for Food and Drug Administration and Control (NAFDAC) of Nigeria and the Ethical Committee of the NIPRD. Written informed consent was obtained from the adult participants, and the caregivers and parents of younger children.

Participants

This trial included 82 participants, although availability of outcome data varied from 52 to 82 participants (Wambebe 2001). The trial included people of all ages (actual age range 2 to 42 years old, but mainly adolescents with the majority in each group being students) with HbSS, confirmed by haemoglobin electrophoresis. Participants were known to have moderate to severe recurrent episodes of crises, having experienced three or more painful or vaso‐occlusive crises in the previous year. These crises (which may have included episodes of acute chest syndrome, splenic or hepatic sequestration or priapism) were defined as an acute painful event requiring treatment with:

1. parenteral narcotics;

2. or equianalgesic dose of oral narcotic;

3. or parenteral non‐steroidal anti‐inflammatory drugs;

4. or equianalgesic oral dose of non‐steroidal anti‐inflammatory drugs.

The trial report outlined conditions for severe crises, but failed to mention how mild to moderate crises were identified (Wambebe 2001).

Potential participants were excluded if they:

1. had clinical features of AIDS;

2. had hepatitis;

3. were pregnant or lactating;

4. had a history of hypersensitivity (more information is required on hypersensitivity and authors have been contacted);

5. were unwilling or unable to follow instructions regarding treatment.

The treatment groups were similar in terms of age and sex at the outset.

Interventions

The active formulation, Niprisan^®, derived from plants indigenous to Nigeria, was previously assessed in both in vitro and in animal studies (Adzu 2001; Awodogan 1996; Gamaniel 1998; Iyamu 2002). Participants were randomised to receive either Niprisan^®, a freeze‐dried extract of Piper guineenses seeds, Pterocarpus osun stem, Eugenia caryophyllum fruit and Sorghum bicolor leaves, at a single daily dose of 12 mg/kg or placebo. Neither the reasons or calculations for this dose; nor the aspect of the composition of the plant extracts used to calculate the dosage from the active ingredients were stated. Niprisan^® and placebo were presented in identical capsule form to be taken orally for six months. Thereafter, participants switched trial arms to receive the other drug (i.e. placebo or Niprisan^®) in the cross over design of the trial. No washout period was clearly described as mentioned above. In addition, all participants received malaria prophylaxis and folic acid. Methods to check for adherence to medications prescribed were not stated.

Outcomes

Outcomes were recorded in the form of self‐assessment using a health diary, by all participants (both adults and children). This was not a previously validated instrument. A period of four months prior to the start of the trial served to establish training in the use of the diary. The assessment was then continued for 12 months, with six months dedicated to each stage of the cross‐over trial. The health diary recorded 36 symptoms and questions and was graded for severity as follows: none (0); mild (1); moderate (2); severe (3). It was not stated how the quality of life measures were assessed and we have contacted trial authors regarding this.

Clinical assessments were based on the health diary recording symptoms and other indicators of ill health and in particular the degree and frequency of pain. Clinicians also made clinical assessments on participants on a weekly basis at the participants' homes using the same criteria to assess pain as the volunteers; and on a monthly basis during participants' attendance at the NIPRD clinic, where additionally blood samples were analysed as detailed below. It was not stated how pain severity was ascertained in the young children who were included in the trial.

Laboratory assessments consisted of a pre‐trial blood test from each participant and then monthly blood tests throughout the trial period. Baseline haemoglobin levels (to ascertain the degree of anaemia) were recorded as well as levels of liver enzymes (to asses liver function): alanine amino‐transferase (ALT); alkaline phosphatase; and gamma glutamine transferase (GGT). Renal function was determined with serum creatinine and blood urea nitrogen (BUN). Nutritional status and metabolic status were assessed by concentrations of: total protein; albumin; total calcium; fasting total cholesterol; fasting triglyceride; fasting blood glucose; and uric acid. All analyses were repeated at cross‐over to establish a baseline at this time and at the end of the trial.

Trial design

This trial was a prospective randomised placebo‐controlled single‐blind intervention trial comparing the safety and efficacy of a phytomedicine derived from plants indigenous to Nigeria (Ciklavit^®, an extract of Cajanuscajan) to placebo in people with SCD (Akinsulie 2005). Although single blind, concealment of allocation was employed. We contacted trial authors and details of the process are described in the section on the Risk of bias in included studies.

Informed consent was obtained from guardians and ethical clearance granted before the commencement of the trial, by the ethics committee of the Lagos University Teaching Hospital, Nigeria.

Participants

The initial recruitment of 100 (50 in each group) drew participants from the Sickle Cell clinic at Lagos University Teaching Hospital. This trial included children with HbSS, between the ages of 1 and 15 years, with HbSS status confirmed by haemoglobin electrophoresis.

Exclusions applied to children:

1. with febrile illness in the preceding two weeks;

2. who had participated in any other drug trial in the preceding six months; or

3. who had evidence of organ failure.

Routine medications (folic acid and anti‐malarials) were not seen as criteria for exclusion.

Interventions

Participants were randomised to receive either Ciklavit^®, an extract of Cajanuscajan, an edible local bean, or placebo. A 10 ml aliquot of the extract contained protein (49 mg) with phenylalanine as its major component. The anti‐sickling property of the Cajanuscajan extract has been attributed to this amino acid. Zinc (400 ug) and ascorbic acid (50 mg) were added as preservatives. The placebo contained zinc (400 ug) and ascorbic acid (50 mg). Children below the age of five years received 10 mL twice daily of active product or placebo, and those over the age of five years received 20 mL twice daily, as per manufacturer's instructions. Both groups of children were placed in the same treatment arm. It was not stated how the manufacturers arrived at this dosage.

Outcomes

Data were collected in several steps. Individuals were given a daily assessment form for documentation of painful episodes and were seen monthly for six months. It was not stated if there was a period of training in the use of the self assessment forms prior to the onset of the trial. We have contacted authors and requested this information.

There was also a standardised questionnaire employed with a complete physical assessment at the outset, three months and six months. This included laboratory assessments comprising blood tests for measurement of packed cell volume (PCV) (a measure of anaemia or blood level), serum bilirubin (a measure of the break down products of destroyed red blood cells and liver function), and urea and creatinine (measures of kidney functions) and urine analysis.

Trial design

This trial was a double‐blinded randomised controlled trial comparing the safety and efficacy of a phytomedicine derived from the roots of Pfaffia paniculata (Brazillian ginseng), a perennial wild plant of the Amaranthaceae family, to placebo on children with SCD in an outpatient setting in Brazil (Araujo 2009). It was not stated in the paper how SCD was diagnosed. Neither the methods used for randomisation, nor details about the procedures for blinding were stated.

Informed consent was obtained from trial participants. However, it was not clear an assent process was used with the minors and adolescents. The trial protocol was approved by the Institutional Ethics Committe of the Hospital das Clinicas da Faculdade de Medicinia da Universidade de Sao Paulo, Brazil, although no IRB number was provided.

Participants

The trial participants comprised 30 children with SCD. There were 15 children in each group ‐ the intervention group had five males and 10 females with an average age of 14 years, while the control group had six males and nine females with an average age of 15 years. It was not stated how SCD was diagnosed.

All trial participants had prior history of frequent abdominal, leg and skeletal pain and other sickle cell symptoms such as jaundice and leg ulcerations. There were no exclusion criteria stated.

Interventions

The participants of the intervention arm received two capsules orally, each containing 500 mg of the powdered root extract of Pfaffia paniculata at eight‐hour intervals for three months; while the control arm received two capsules of placebo containing corn starch orally at the same dosing interval. There was no information on the concealment of intervention and how the dosage was determined.

Outcomes

The trial compared clinical outcomes and laboratory data of both the intervention and control arms for three months. The number of erythrocytes, reticulocytes, sickle cells, peripheral erythroblast, haemoglobin, haematocrit, mean corpuscular volume (MCV), mean corpuscular haemoglobin (MCH) and MCH concentration (MCHC) were measured immediately before, and two and three months after the start of treatment.

The authors reported on foetal haemoglobin, pain crises, other symptoms associated with SCD ‐ priapism, lower limb ulcers, chest syndromes, skeletal and abdominal pain, frequency of blood transfusion, occurrence of pneumonia, adverse effects and quality of life indicators. There were no clear assessment and monitoring protocols established for these parameters.

The authors of the trial were contacted for more details regarding the trial, but no additional information was provided.

Generation of allocation sequence

This trial was described as randomised. The trial authors report that participants were randomised into two treatment groups by 'simple random sampling' (Wambebe 2001). The process of randomisation was not stated and we have been unable to obtain further information on this from the authors. We judged this process as 'unclear'.

Concealment of allocation sequence

The participants and trial authors could not foresee the assignment of each participant as the allocation was done centrally by a third party not directly involved with the trial (Wambebe 2001). We judged this process as having a low risk of bias.

Generation of allocation sequence

This was described as using block randomisation (Akinsulie 2005). The generation of random sequence was by shuffling sequentially numbered envelopes in blocks of ten. This was repeated when the block was exhausted. The allocation sequence was adequately generated and we judge this as having a low risk of bias.

Concealment of allocation sequence

Totally opaque brown envelopes of the same size were used (Akinsulie 2005). The envelopes were held by the clinic nurse who allocated the treatment once the inclusion criteria had been met. The nurse was not one of the trial investigators. Once one of the investigators saw an individual eligible for inclusion in the trial, after obtaining informed consent, the individual was sent to the clinic nurse, in another room, who held the envelopes. She selected the first randomly assigned envelope containing either the test product or placebo, which was unknown to either the participant or the nurse. For the subsequent eligible participant, the next envelope was selected until the block envelope was exhausted and the process was repeated for the next block. The participants and trial authors could not foresee the assignment of each participant as the allocation was done by central allocation by a third party not directly involved with the trial. We judge this process as having a low risk of bias.

Generation of allocation sequence

The trial was described as randomised, however, the method of randomisation was not stated (Araujo 2009). The trial authors were asked for more information about the randomisation process but no additional information was provided. We judge this as having an unclear risk of bias.

Concealment of allocation sequence

This was not described in the published trial report (Araujo 2009). The trial authors were asked for more information on the concealment of allocation sequence but they were unable to provide further details. We judge this as having an unclear risk of bias.

1. Frequency, severity or duration of painful crises

Data from health diaries were available from 70 participants (Wambebe 2001). Participants reported mild, moderate and severe pain using a scale from zero to three, as described above. Results are reported for mild or moderate pain and severe pain separately. In the first six months, the treatment group (n = 34) showed a significant difference relative to the placebo group (n = 36) for severe pain episodes occurring with a mean (SD) of 7.9 (8.4) times, compared to 21.1 (32.9) times in the placebo group (low‐quality evidence). Given that data were skewed (and therefore cannot be analysed in RevMan), analysis of these data was undertaken by the trial authors using a non‐parametric method (RevMan 2014). No statistically significant difference was noted between groups as regards mild or moderate pain in the first six‐month period.

2. Frequency of severe complications of SCD including sequestration crises, acute sickle chest syndrome and leg ulcer

Summary statistics were provided for the frequency of reported crises, by treatment group and trial period per month (Wambebe 2001). This was based on completed health diaries from 70 participants. In the first six months, no statistically significant difference by distribution was found between the treatment (n = 34) and placebo (n = 36) groups (low‐quality evidence). No separate information is provided on sequestration crises, sickle chest or leg ulcer.

3. Frequency of hospital admissions from severe complications of SCD including sequestration crises, acute sickle chest syndrome and leg ulcer

The difference between groups, before cross‐over in relation to frequency of hospital admissions per month was not significant (low‐quality evidence) (Wambebe 2001).

1. Any adverse events including hepatic and renal toxicity

Two participants on Niprisan^® developed non‐itching macular rashes three to four days after starting treatment, which disappeared a few days later (Wambebe 2001). Six participants on Niprisan^® developed headache compared to two on placebo. Laboratory results were reported for a total of 52 participants (27 in the Niprisan^® group and 25 in the placebo group). One participant in the Niprisan^® group had altered liver function at the start of the trial, but this did not deteriorate or change over the trial period. Tests showed no significant difference in liver or kidney (renal) function between the arm receiving Niprisan^® (the active formulation) or the placebo arm at the end of the first six months. There was also no change relative to baseline values recorded four months prior to administration of the formulation or placebo. After the first treatment period at six months, the differences in the mean activities of all the measured liver enzymes were not statistically significant. The mean difference for ALT was ‐1.00 IU (95%CI ‐5.74 to 3.74); for AST, 7.00 IU (95% CI ‐6.28 to 20.28); for ALP, 2.00 IU (95% CI ‐5.93 to 9.93); and for GGT, ‐3.00 IU (95% CI ‐8.42 to 2.42). There were also no significant changes in levels of serum creatinine, MD 1.00 µmol/L (95% CI ‐10.95 to 12.95) or of BUN, MD 0.30 mmol/l (95% CI ‐ 0.25 to 0.85) (low‐quality evidence) (Analysis 1.1).

2. Frequency of blood transfusion

This outcome was not reported (Wambebe 2001).

3. Level of anaemia

Haemoglobin level was reported for 52 participants (27 participants receiving Niprisan^® and 25 receiving placebo in the first six months prior to cross‐over) (Wambebe 2001). Haemoglobin was reported as a mean (SD) in g/dL for each group relative to baseline within groups, as well as between groups. At six months the mean difference (MD) of haemoglobin concentration was 0.30 g/dL (95% CI ‐1.83 to 2.43), which was not statistically significant (low‐quality evidence) (Analysis 1.2).

4. Quality of life measures

The comparability of the two groups was assessed pre‐trial using the health diary, completed by trial participants. There was no mention of any differences in this assessment tool (health diaries) for the adults and children. Given that these data were skewed, analysis was performed within the primary paper using a non‐parametric method (Wambebe 2001). There were no significant differences between groups at the outset. At six months, 70 participants had completed health records, and participants reported health being below average in the active treatment group (n = 34), with a mean (SD) of 12.2 (11.6) times, compared to the placebo group (n = 36) with a mean (SD) of 31.3 (31.4) times (very low‐quality evidence). This difference was not statistically significant.

Summary statistics were provided for absenteeism from work or school, based on results available for 70 participants (Wambebe 2001). The distribution is skewed for these results, so data have not been presented at this stage, as only summary statistics are available. In the first six months, in the between group analysis, there was no significant difference between the active treatment (n = 34) and placebo (n = 36) groups, as regards absenteeism from work or school.

1. Frequency, severity or duration of painful crises

They reported there were 207 episodes of painful crises (mean 4.4, SD 10.3) before the trial, and 191 episodes (mean 4.2, SD 4.2) during the trial among the intervention group; and 109 episodes (mean 2.6, SD 50) before the trial and 164 episodes (mean 3.9, SD 4.3) during the trial among the control group (low‐quality evidence). Given the skewed nature of these data, we were unable to enter these data into the 'Data and analyses' section.

2. Frequency of severe complications of SCD including sequestration crises, acute sickle chest syndrome and leg ulcer

This outcome was not reported (Akinsulie 2005).

3. Frequency of hospital admissions from severe complications of SCD including sequestration crises, acute sickle chest syndrome and leg ulcer

This outcome was not reported (Akinsulie 2005).

1. Any adverse events including hepatic and renal toxicity

The trial reports that there was no significant change in level of bilirubin, urea or creatinine during the study, but figures were not provided (Akinsulie 2005). There were no significant differences between the groups regarding the following adverse events. Vomiting occurred in one participant in each group. The authors reported tiredness (one participant) and abdominal distention (one participant) in the treatment group, and peri‐orbital swelling (one participant), diarrhoea (one participant), and itching of the eyes (one participant) in the control group (low‐quality evidence). These were reported as being transient events. For full summary statistics, please refer to Analysis 2.1.

2. Frequency of blood transfusion

This outcome was not reported (Akinsulie 2005).

3. Level of anaemia

PCV was reported (Akinsulie 2005). The across group comparisons are not reported in the original trial report, but on entering data presented into the RevMan analysis we showed no significant difference between treatment and control groups at three months, MD ‐1.52 (95% CI ‐3.49 to 0.45); and six months, MD ‐1.54 (95% CI ‐3.16 to 0.08) (low‐quality evidence) (Analysis 2.2). This suggested a fall in PCV in the treatment group, although formal testing for trend for this outcome was not performed in our analysis.

4. Quality of life measures

This outcome was not reported (Akinsulie 2005).

1. Frequency, severity or duration of painful crises

The trial authors stated that the intervention arm exhibited less pain post‐treatment, and also less than the control arm. Specifically there were less episodes of vaso‐occlusive crises and priapism (very low‐quality evidence) (Araujo 2009).

2. Frequency of severe complications of SCD including sequestration crises, acute sickle chest syndrome and leg ulcer

The trial authors stated that the intervention arm exhibited less incidence of lower limb ulceration and chest syndromes post‐treatment and less than the control arm post‐treatment. There was also less incidence of jaundice and thromboembolism in the intervention arm of the trial (very low‐quality evidence) (Araujo 2009).

3. Frequency of hospital admissions from severe complications of SCD including sequestration crises, acute sickle chest syndrome and leg ulcer

This outcome was not reported (Araujo 2009).

1. Any adverse events including hepatic and renal toxicity

The authors reported that there were no adverse effects in the participants who received the extract of the powdered roots of Pfaffia paniculata (very low‐quality evidence) (Araujo 2009)

2. Frequency of blood transfusion

It was reported that there were no need for blood transfusions in the intervention arm post‐treatment and in comparison to the control group. However, the number of transfusions in the control arm was not stated (very low‐quality evidence) (Araujo 2009).

3. Level of anaemia

Increased levels of haematocrit and haemoglobin concentrations by 28% and 26% respectively were reported in the intervention arm; while no changes in these parameters were observed in the control arm during the observation period (very low‐quality evidence) (Araujo 2009).

4. Quality of life measures

Participants of the intervention arm were reported to have improved mental and physical activities and therefore an improved quality of life as compared to the control arm of the trial (very low‐quality evidence) (Araujo 2009).