# Abstract

 Artemisinin combination therapies are available in private outlets, but patient adherence might be compromised by poor advice from dispensers. In this cluster randomized trial in drug shops in Tanzania, 42 of 82 selected shops were randomized to receive text message reminders about what advice to provide when dispensing artemether-lumefantrine (AL). Eligible patients purchasing AL at shops in both arms were followed up at home and questioned about each dose taken. Dispensers were interviewed regarding knowledge of AL dispensing practices and receipt of the malaria-related text messages. We interviewed 904 patients and 110 dispensers from 77 shops. Although there was some improvement in dispenser knowledge, there was no difference between arms in adherence measured as completion of all doses (intervention 68.3%, control 69.8%, *p* [adjusted] = 0.6), or as completion of each dose at the correct time (intervention 33.1%, control 32.6%, *p* [adjusted] = 0.9). Further studies on the potential of text messages to improve adherence are needed. # Results [Figure 1](#) shows the trial profile. Of the 82 randomized ADDOs, 37 from the control arm and 40 from the intervention arm participated in the study. The number of registered patients eligible for follow-up was 537 in the control arm and 518 in the intervention arm, with ∼15% of patients in each arm lost to follow-up. Most outlets were in urban wards (70% in both arms), had a single dispenser, and had at least some ACTs in stock on the day of interview ([Table 1](#)). Of 51 dispensers in the control arm and 59 in the intervention arm, ∼80% in both arms were female and had a low-level medical qualification, mostly nurse assistants ([Table 2](#)). Though low in both arms, more ADDOs in the control arm compared with the intervention arm were able to show an accreditation certificate (43% versus 20%, respectively). However, the difference in the percentages of dispensers that had received training on ACTs was not as pronounced (69% in the control arm versus 60% in the intervention arm), though the median year of training was more recent in the control arm (2011 versus 2009). Characteristics of patients were well balanced between arms ([Table 3](#)). A high percentage of patients (36% in the control arm and 38% in the intervention arm) had sought care before attending the study ADDO, with most patients going to a kiosk or general shop and only 7% of patients in the control arm and 4% in the intervention arm going to a public health facility. Approximately 90% reported symptoms of fever or headache, and approximately half had upset stomachs or nausea. Based on an mRDT taken at the time of follow-up, 28% in the control arm and 25% in the intervention arm tested positive, with only 1.4% and 1.6%, respectively, testing positive by study blood smear. (Some degree of discrepancy is expected because of the persistence of HRP2 detected by the mRDT.) Seventy percent of dispensers received at least 75% of the text messages. The median percentage of messages received was 86%, with 20% of dispensers receiving no messages ([Figure 3](#)). [Table 4](#) presents results of the dispenser interviews on knowledge of advice to provide patients when dispensing AL. Dispensers in the intervention arm reported slightly better knowledge of the correct AL regimen for adults in the intervention arm compared with the control arm (90% versus 78%; adjusted prevalence ratio [aPR] = 1.2 (95% confidence interval \[CI\]: 0.95, 1.5); *p* [adjusted] = 0.0748), though knowledge of the correct regimen for a child aged four weighing 20 kg was lower than for adults in both arms (75% versus 64%; aPR = 1.2 [0.85, 1.7]; *p* [adjusted] = 0.2). Dispenser knowledge was considerably higher in the intervention arm than the control arm on advice to take AL with fatty food (60% versus 20%; aPR = 3.4 [95% CI: 1.6, 7.1]; *p* [adjusted] < 0.0001) and to continue to take AL if minor side effects occur (68% versus 43%; aPR = 1.6 [95% CI: 1.0, 2.4]; *p* [adjusted] = 0.0188). However, surprisingly high dispenser knowledge (87--99%) was recorded in both arms on advice to complete treatment even if feeling better, advice to return to the ADDO or go to a health facility if the condition worsens, and advice to take the second dose after 8 hours ([Table 4](#)). Knowledge on advising patients to take a replacement dose in case of vomiting within half an hour of taking a dose was lower (55% versus 50%), with no difference observed between arms. <figure> <p><img src="" /></p> <figcaption>Percentage of text messages received by dispensers in the intervention arm.</figcaption> </figure> [Table 5](#) shows that ∼60% of patients in both arms reported being told how to take AL correctly, with similar percentages reporting being told to take the second dose after 8 hours and to complete treatment even if feeling better, indicating that dispensers were providing some advice even in the absence of the intervention. However, no differences were found between control and intervention arms for any piece of advice. Less than 5% of patients in both arms reported being told about vomiting, side effects, or taking AL with fatty food, and < 10% in both arms took the first dose of AL at the ADDO. There was no difference in patient adherence between arms ([Table 6](#)). Completed treatment was 70% in the control arm and 68% in the intervention arm (adjusted risk ratio [aRR] = 0.96 [95% CI: 0.82, 1.1]; *p* [adjusted] = 0.6), with a similar percentage of patients adherent to each of the four age-appropriate blister packs and no important differences between arms. The mean number of doses taken by non-adherent patients was four in both arms, and the most common reported reasons for non-adherence included planning to take the medication later, forgetting to take the tablets, feeling better, and other reasons ([Figure 4](#)). Timely completion was much lower, with 33% of patients in both arms taking all doses at appropriate times. A per protocol analysis, excluding patients attending ADDOs where at least one dispenser did not receive any messages, had no impact on results. <figure> <p><img src="" /></p> <figcaption>Reasons given by patients/caretakers for not completing treatment.</figcaption> </figure> ::::table-wrap

::: caption
Characteristics of accredited drug dispensing outlets (ADDOs)
:::

```
                                                                         Control      Intervention
```

______________________________________________________________________

Number (*N*) 37 40
Number urban (%) 26 (70%) 28 (70%)
Median number of dispensers per ADDO (range) 1 (1--3) 1 (1--4)
Number with one or more trained medical staff (%)[\*](#) 36 (97%) 37 (92%)
Number with any ACTs in stock on day of interview (%) 35 (95%) 40 (100%)
Number with all four weight-based packs in stock on day of interview (%) 11 (30%) 14 (35%)
Median number of customers purchasing ACTs in last 7 days (range) 13 (0--82) 19 (0--147)
Number with ADDO accreditation certificate (%) 16 (43%) 8 (20%)
Number with drinking water available in ADDO (%) 30 (81%) 37 (93%)

Medical staff is defined as pharmacists, pharmacist assistants, medical
doctors, assistant medical doctors, clinical officers, assistant
clinical officers, midwives, nurses, nurse assistants, and laboratory
technologists. Most were nurse assistants or nurses.

ACTs = artemisinin-based combination therapies.:::: ::::table-wrap
::: caption
Characteristics of dispensers (post-intervention)
:::

```
                                                      Control             Intervention
```

______________________________________________________________________

Total number of dispensers 53 59
Number interviewed (*N*) 51 59
Male (%)[\*](#) 10 (20%) 13 (22%)
Age (%)[\*](#)\
Under 35 years of age 18 (35%) 23 (39%)
35--49 years of age 23 (45%) 17 (29%)
50 years and above 10 (20%) 19 (32%)
Number with a medical qualification (%)[\*](#)[†](#) 44 (86%) 47 (81%)
Socioeconomic status (%)[‡](#)[§](#)\
1st quintile (most poor) 9 (18%) 13 (22%)
2nd quintile 12 (24%) 10 (17%)
3rd quintile 9 (18%) 13 (22%)
4th quintile 8 (16%) 14 (24%)
5th quintile (least poor) 12 (24%) 9 (15%)
Number that had attended training on ACTs (%)[\*](#) 35 (69%) 35 (60%)
Median year of training (range) 2011 (2005--2012) 2009 (2001--2012)

Data missing for one dispenser in intervention arm.

Medical staff is defined as pharmacists, pharmacist assistants, medical
doctors, assistant medical doctors, clinical officers, assistant
clinical officers, midwives, nurses, nurse assistants, and laboratory
technologists. Most were nurse assistants or nurses.

Data missing for one dispenser in control arm.

Wealth quintiles determined using a principal component analysis of
sampled dispensers based on standard Demographic and Health Survey
variables.:::: ::::table-wrap
::: caption
Characteristics of patients
:::

```
                                                                               Control     Intervention
```

______________________________________________________________________

Number (*N*) 451 453
Male 240 (53%) 211 (47%)
Age[\*](#)\
Under 3 years 81 (18%) 78 (17%)
3 years to under 8 years 104 (23%) 91 (20%)
8 years to under 12 years 41 (9%) 42 (9%)
12 years and above 225 (50%) 242 (53%)
Blister pack obtained\
1 × 6 (6 tablets) 109 (24%) 107 (23%)
2 × 6 (12 tablets) 95 (21%) 88 (19%)
3 × 6 (18 tablets) 50 (11%) 43 (10%)
4 × 6 (24 tablets) 197 (44%) 215 (48%)
Patient (or caregiver if patient below age 12) completed primary school[†](#) 323 (72%) 343 (76%)
Socioeconomic status[‡](#)\
1st quintile (most poor) 87 (19%) 94 (21%)
2nd quintile 99 (22%) 82 (18%)
3rd quintile 97 (22%) 84 (19%)
4th quintile 85 (19%) 96 (21%)
5th quintile (least poor) 83 (18%) 97 (21%)
Slept under any bed net the night before the follow up interview 321 (71%) 357 (79%)
Sought care before attending study ADDO 171 (38%) 163 (36%)
Median days since illness onset before seeking care at ADDO[§](#) 1 1
Symptoms[¶](#)\
Fever or headache 410 (91%) 416 (92%)
Respiratory 34 (8%) 34 (8%)
Stomach upset 220 (49%) 209 (46%)
Other[∥](#) 216 (48%) 211 (47%)
mRDT positive at follow up[\*\*](#) 121 (28%) 108 (25%)
Blood smear positive at follow up[††](#) 6 (1.4%) 7 (1.6%)

Age categories based on recommended age breakdown for
artemether-lumefantrine (AL) blister packs in Tanzania.

Caregiver education missing for 3 patients < 12 in intervention arm.

Wealth quintiles determined using a principal component analysis of
sampled patients based on standard Demographic and Health Survey
variables.

Eleven patients in control arm and 4 patients in intervention arm did
not remember the number of days after illness onset when they sought
care at the study accredited drug dispensing outlets (ADDO).

Percents do not add to 100% as patients experienced multiple symptoms.

Includes fatigue, body aches, dizziness, shaking, convulsions,
unusually-colored urine, yellow mouth/eyes/body, etc.

Malaria rapid diagnostic test (mRDT) data missing for 12 patients in
control arm and 12 patients in intervention arm.

Blood smear data missing for 18 patients in control arm and 13 patients
in intervention arm.:::: ::::table-wrap
::: caption
Dispenser knowledge of correct advice (mean of cluster summaries)
:::

```
                                                                           Control[*](#) (*N* = 37) % (SD)   Intervention[*](#) (*N* = 40) % (SD)   Adjusted prevalence ratio (95% CI)[†](#)   Adjusted *P* value[†](#)
```

______________________________________________________________________

Proportion that gave correct advice on:\
Correct AL regimen for adult[‡](#) 78.4 (38.3) 90.0 (33.7) 1.19 (0.95, 1.49) 0.075
Correct AL regimen for a child (4 years and 20 kg)[‡](#) 63.5 (46.6) 74.6 (40.4) 1.20 (0.85, 1.70) 0.2
Take with fatty food 20.3 (38.1) 60.0 (45.6) 3.41 (1.63, 7.12) 0.0001
Continue treatment if minor side effects occur 42.8 (42.8) 67.5 (45.2) 1.58 (1.03, 2.42) 0.019
Return to ADDO or go to a health facility if condition worsens 91.0 (25.3) 100.0 1.04 (0.84, 1.31) 0.7
Take second dose after 8 hours 86.9 (32.2) 97.5 (15.8) 1.11 (0.93, 1.32) 0.1
Take replacement dose in case of vomiting within half hour of taking dose 49.5 (45.7) 55.0 (46.4) 1.20 (0.77, 1.86) 0.4
Complete treatment even if feeling better 98.6 (8.2) 98.8 (7.9) 1.07 (0.88, 1.30) 0.5

Total number of dispensers interviewed was 51 in the control arm and 59
in the intervention arm.

Adjusted for accredited drug dispensing outlet (ADDO) accreditation,
number of customers at ADDO purchasing artemisinin-based combination
therapies (ACTs) (< 20 vs. 20 or more), dispenser medical
qualification, and training on ACTs

To be considered correct, responses had to identify
artemether-lumefantrine (AL) as first-line treatment and specify that
six doses should be taken, with each dose consisting of four pills
(adult) or 2 pills (child 4 years of age). Dose intervals considered
correct included (A) taking a dose morning and evening for 3 days or (B)
taking the second dose 8 hours after the first dose and the remaining
doses 12 hours apart (or morning and evening for the next 2 days).:::: ::::table-wrap
::: caption
Patient report of advice received from dispenser (mean of cluster
summaries)
:::

```
                                                                       Control* (*N* = 37) % (SD)   Intervention[*](#) (*N* = 40) % (SD)   Adjusted prevalence ratio (95% CI)[†](#)   Adjusted *P* value[†](#)
```

______________________________________________________________________

Explained correct dose regimen[‡](#) 60.6 (21.2) 62.9 (21.5) 1.00 (0.84, 1.20) 0.9
Told to take second dose after 8 hours 64.2 (19.6) 63.0 (20.2) 1.00 (0.87, 1.15) 0.9
Told to complete treatment even if feeling better 61.3 (25.3) 59.3 (27.3) 0.94 (0.76, 1.17) 0.5
Told not to give drug to anyone else or save for future illnesses 41.3 (23.3) 35.1 (25.1) 0.88 (0.65, 1.18) 0.4
Told to return to ADDO or go to a health facility if condition worsens 34.1 (20.5) 35.0 (22.4) 1.01 (0.75, 1.35) 0.9
Told to take replacement dose in case of vomiting 3.3 (8.9) 3.2 (3.2) 1.48 (0.56, 3.90) 0.5
Told about possible side effects 2.8 (5.1) 2.0 (5.1) 0.60 (0.13, 2.77) 0.4
Told to take each dose with fatty food or milk[§](#) 2.2 (8.4) 4.2 (9.7) 1.70 (0.40, 7.24) 0.4
First dose was observed at ADDO 5.4 (9.1) 6.9 (12.7) 1.32 (0.63, 2.76) 0.5

Total number of patients interviewed was 451 in the control arm and 453
in the intervention arm.

Adjusted for accredited drug dispensing outlet (ADDO) accreditation,
number of customers at ADDO purchasing artemisinin-based combination
therapies (ACTs) (< 20 vs. 20 or more), dispenser medical
qualification, and training on ACTs

To be considered correct, responses had to include the correct number of
pills per dose for blister pack obtained, two doses per day, and 3 days
duration (or 4 days to account for artemether-lumefantrine [AL]
obtained late on Day 1)

If taking with any food or milk is considered correct, percentages
increase to 60.2 (22.1) in the control arm and 58.8 (26.0) in the
intervention arm, *P* = 0.8):::: ::::table-wrap
::: caption
Patient adherence (mean of cluster summaries)
:::

```
                          Control* (*N* = 37) % (SD)   Intervention[*](#) (*N* = 40) % (SD)   Adjusted prevalence ratio (95% CI)[†](#)   Adjusted *P* value[†](#)
```

______________________________________________________________________

Completed treatment[‡](#) 69.8 (20.9) 68.3 (23.4) 0.96 (0.82, 1.12) 0.6
1 × 6 (6 tablets) 68.2 (33.3) 73.4 (30.9) 1.04 (0.81, 1.33) 0.7
2 × 6 (12 tablets) 62.0 (33.4) 70.7 (40.5) 1.10 (0.85, 1.43) 0.5
3 × 6 (18 tablets) 73.0 (35.7) 62.5 (39.7) 0.86 (0.66, 1.13) 0.4
4 × 6 (24 tablets) 73.8 (23.1) 67.8 (29.1) 0.89 (0.74, 1.08) 0.2
Timely completion[§](#) 32.6 (18.4) 33.1 (21.6) 1.01 (0.76, 1.36) 0.9
1 × 6 (6 tablets) 37.2 (36.7) 26.4 (34.5) 0.67 (0.35, 1.28) 0.2
2 × 6 (12 tablets) 25.7 (24.9) 33.1 (36.6) 1.32 (0.86, 2.00) 0.4
3 × 6 (18 tablets) 35.5 (41.3) 37.9 (41.4) 1.02 (0.57, 1.81) 0.9
4 × 6 (24 tablets) 38.1 (27.6) 34.8 (29.3) 0.90 (0.57, 1.41) 0.6

Total number of patients interviewed was 451 in the control arm and 453
in the intervention arm.

Adjusted for accredited drug dispensing outlet (ADDO) accreditation,
number of customers at ADDO purchasing artemisinin-based combination
therapies (ACTs) (< 20 vs. 20 or more), and patient education (patient
or caregiver completed primary school).

Completed treatment unknown for three patients in the control arm and
two patients in the intervention arm.

Timely completion unknown for 10 patients in the control arm and 11
patients in the intervention arm.::::


Extracted trial result:
Outcome: patient adherence (continuous)
Intervention: receive text message reminders about what advice to provide when dispensing artemether-lumefantrine (AL).
Comparator: no text message
Intervention group size: 40
Intervention mean: 68.3
Intervention standard deviation: 23.4
Comparator group size: 37
Comparator mean: 69.8
Comparator standard deviation: 20.9
Notes: Data found in Table 6. Used same values as "completed treatment"