1. ZAMSTAR restricted randomisation CREATE Investigators Meeting 2005 Charalambos (Babis) Sismanidis LSHTM

2. ZAMSTAR overview  Zambia and South Africa tuberculosis and AIDS reduction study  24 communities (16 in Zambia, 8 in SA) are randomised in 4 arms (2x2 factorial).  Primary outcome: culture +ve TB prevalence (survey on 5,000 patients sampled in each cluster) after 3 years of intervention application

3. Description of interventions  TB/HIV @ clinic Strengthened DOTS VCT TB/HIV at health centre access (offering IPT) Basic HIV care HIV prevention (condoms, STI management)  Enhanced Tuberculosis Case Finding (ECF) Open access to sputum smear at health centre Schools education campaign Community mobilisation and mobile tuberculosis laboratory  Household level TB & HIV combined activities (HH) Household counsellor visiting all TB households Household members encouraged to test for HIV TB preventive therapy for HIV+ve and children <6  Both ECF & HH

4. ZAMSTAR primary aims  Does enhanced tuberculosis case finding (ECF) by a strategy of community mobilisation and improved access to sputum microscopy, reduce prevalence of tuberculosis in the community?  Do combined TB/HIV activities at the household level (HH), reduce prevalence of tuberculosis?  Does ECF plus HH (ECF+HH), yield additional benefits for tuberculosis control through additional case detection, improved case holding, treatment/prophylaxis of latent infection and reduction in HIV incidence?

5. Does ECF reduce the prevalence of tuberculosis in the community?

6. Does HH reduce the prevalence of tuberculosis in the community?

7. Stratification  The 24 clusters are stratified by country of cluster origin. 16 from Zambia, 8 in SA  Randomisation will be performed separately for each of the two strata

8. Zambia – Step I  4 equally numbered groups of As, Bs, Cs & Ds to form from 16 available communities (i.e. 4 communities in each group).  Arm A will include 4 communities out of the 16: 16!/12!4! = 1820 choices Arm B another 4 from the remaining 12 communities: 12!/8!4! = 495 choices Arm C another 4 from the remaining 8: 8!/4!4! = 70 choices Arm D 4 from the remaining 4: 4!/4!0! = 1 choice  This amounts to=1820*495*70*1=63,063,000

9. Zambia – Step II  BUT since we do not have a fixed sequence by which intervention arms will be picked (sequence ABCD is a generic example) we need to multiply the previous total by 4! (i.e. all possible permutations for an array of 4 elements).  TOTAL: 63,063,000*4! = 1,513,512,000

10. South Africa – Step I  4 equally numbered groups (= intervention arms) of As, Bs, Cs & Ds to form from 8 available communities (i.e. 2 communities in each group).  Arm A will have 2 communities out of 8 = 8!/6!2! = 28 choices Arm B another 2 from the remaining 6 communities (6!/4!2!) = 15 choices Arm C another 2 from the remaining 4 = 4!/2!2! = 6 choices Arm D 2 from the remaining 2 = 1 choice  Which amounts to = 28*15*6*1=2520

11. South Africa – Step II  Similarly since we do not have a fixed sequence by which intervention arms will be picked we need to multiply the previous total by 4!  TOTAL: 2520*4! = 2520*24 = 60,480

12. Computational headaches  Because of the very large number of possible permutations it has not so far been possible to list them all  Single file size not allowed to be >12GB  Current code produces multiple identical observations (which are then dropped)

13. Restricting randomisation  Possible restrictions: HIV prevalence TB infection (TST in children) Open/Closed communities (Social Science) Political restrictions (not all clusters in a community in the control arm-should this be extended to all arms?)

14. Changing lanes  THRio approach?  Instead of listing all possible permutations to get the exact proportion by which randomisation is restricted, I will now be randomly drawing a set number of permutations to estimate this proportion.  Then randomly draw one permutation from a list of ‘acceptable’ ones